Materials and methods for engineering cells and uses thereof in immuno-oncology

ABSTRACT

Materials and methods for producing genome-edited cells engineered to express a chimeric antigen receptor (CAR) construct on the cell surface, and materials and methods for genome editing to modulate the expression, function, or activity of one or more immuno-oncology related genes in a cell, and materials and methods for treating a patient using the genome-edited engineered cells.

RELATED APPLICATIONS

This application is a divisional of application Ser. No. 16/435,146,filed on Jun. 7, 2019, which is a divisional of application Ser. No.15/977,798, filed May 11, 2018, now abandoned which claims the benefitunder 35 U.S.C. § 119(e) of U.S. provisional application No. 62/505,649,filed May 12, 2017, U.S. provisional application No. 62/508,862, filedMay 19, 2017, U.S. provisional application No. 62/538,138, filed Jul.28, 2017, U.S. provisional application No. 62/567,012, filed Oct. 2,2017, U.S. provisional application No. 62/567,008, filed Oct. 2, 2017,U.S. provisional application No. 62/583,793, filed Nov. 9, 2017, U.S.provisional application No. 62/639,332, filed Mar. 6, 2018, U.S.provisional application No. 62/648,138, filed Mar. 26, 2018, and U.S.provisional application No. 62/655,510, filed on Apr. 10, 2018, each ofwhich is incorporated by reference herein in its entirety.

FIELD

In some aspects, the present application provides materials and methodsfor producing genome-edited cells engineered to express a chimericantigen receptor (CAR) construct on the cell surface. In other aspects,the present application provides materials and methods for genomeediting to modulate the expression, function, or activity of one or moreimmuno-oncology related genes in a cell. In yet other aspects, thepresent application provides materials and methods for treating apatient using the genome-edited engineered cells, both ex vivo and invivo.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Sep. 28, 2020, isnamed 095136-0143_005 USDIV8_SeqLstg and is 1,253,376 bytes in size. TheSequence Listing is being submitted by EFS Web and is herebyincorporated by reference into the specification.

BACKGROUND

Genome engineering refers to strategies and techniques for the targeted,specific modification of the genetic information (genome) of livingorganisms. Genome engineering is an active field of research because ofthe wide range of possible applications, particularly in the area ofhuman health, e.g., to correct a gene carrying a harmful mutation or toexplore the function of a gene. Early technologies developed to insert atransgene into a living cell were often limited by the random nature ofthe insertion location of the new sequence into the genome. Randominsertions into the genome may result in disruption of normal regulationof neighboring genes leading to severe unintended effects. Furthermore,random integration technologies offer little reproducibility, as thereis no guarantee that the sequence would be inserted at the same place intwo different cells. Common genome engineering strategies, such as ZFNs,TALENs, HEs, and MegaTALs, allow a specific area of the DNA to bemodified, thereby increasing precision of the correction or insertioncompared to earlier technologies. These platforms offer a greater degreeof reproducibility, but limitations remain.

Despite efforts from researchers and medical professionals worldwide toaddress genetic disorders, and despite the promise of previous genomeengineering approaches, there remains a long-felt need to develop safeand effective universal donor cells in support of cell therapytreatments involving regenerative medicine and/or immuno-oncologyrelated indications.

SUMMARY

Provided herein, in some embodiments, are cells, methods, andcompositions (e.g., nucleic acids, vectors, pharmaceutical compositions)used for the treatment of certain malignancies. The gene editingtechnology of the present disclosure, in some aspects, is used toengineer immune cell therapies targeting tumor cells that express theCD19, CD70, or BCMA antigens. Surprisingly, the immune cell therapiesengineered according to the methods of the present disclosure arecapable of reducing tumor volume in vivo, in some embodiments, by atleast 80%, relative to untreated controls. Data from animal models, asprovided herein, demonstrates that the engineered immune cell therapies,in some embodiments, eliminate the presence of detectable tumor cellsjust 30 days following in vivo administration, and the effect in theseanimal models, following a single dose of the cell therapy, persists forat least 66 days. Further, in some embodiments, the engineered immunecell therapies of the present disclosure are capable of increasing thesurvival rate of subject by at least 50% relative to untreated controls.

Further still, these cells are engineered to block bothhost-versus-graft disease and graft-versus-host disease, which rendersthem suitable for use as allogeneic cell transplantation therapeutics.

Moreover, genetic constructs and methods provided herein may be used, insome embodiments, to engineer immune cell populations with genemodification efficiencies high enough that the cell populations do notrequire purification or enrichment prior to administration in vivo. Forexample, at least 80% of the immune cells of an exemplary engineeredcell population of the present disclosure lack surface expression ofboth the T cell receptor alpha constant gene and the β2 microglobulingene, and at least 50% of the immune cells also express the particularchimeric antigen receptor of interest (e.g., targeting CD19, CD70, orBCMA).

Thus, provided herein, in some aspects, are populations of cellscomprising engineered T cells that comprise a T cell receptor alphachain constant region (TRAC) gene disrupted by insertion of a nucleicacid encoding a chimeric antigen receptor (CAR) comprising (i) anectodomain that comprises an anti-CD19 antibody fragment, (ii) a CD8transmembrane domain, and (iii) an endodomain that comprises a CD28 or41BB co-stimulatory domain and optionally a CD3z co-stimulatory domain,and a disrupted beta-2-microglobulin (B2M) gene, wherein at least 70% ofthe engineered T cells do not express a detectable level of TCR surfaceprotein and do not express a detectable level of B2M surface protein,and/or wherein at least 50% of the engineered T cells express adetectable level of the CAR.

Other aspects provide populations of cells comprising engineered T cellsthat comprise

a TRAC gene disrupted by insertion of a nucleic acid encoding a CARcomprising (i) an ectodomain that comprises an anti-CD70 antibodyfragment, (ii) a CD8 transmembrane domain, and (iii) an endodomain thatcomprises a CD28 or 41BB co-stimulatory domain and optionally a CD3zco-stimulatory domain, and a disrupted B2M gene, wherein at least 70% ofthe engineered T cells do not express a detectable level of TCR surfaceprotein and do not express a detectable level of B2M surface protein,and/or wherein at least 50% of the engineered T cells express adetectable level of the CAR.

Yet other aspects provide populations of cells comprising engineered Tcells that comprise a TRAC gene disrupted by insertion of a nucleic acidencoding a CAR comprising (i) an ectodomain that comprises an anti-BCMAantibody fragment, (ii) a CD8 transmembrane domain, and (iii) anendodomain that comprises a CD28 or 41BB co-stimulatory domain andoptionally a CD3z co-stimulatory domain, and a disrupted B2M gene,wherein at least 70% of the engineered T cells do not express adetectable level of TCR surface protein and do not express a detectablelevel of B2M surface protein, and/or wherein at least 50% of theengineered T cells express a detectable level of the CAR.

Some aspects of the present disclosure provide methods for producing anengineered cell suitable for allogenic transplantation, the methodcomprising (a) delivering to a composition comprising a T cell aRNA-guided nuclease, a gRNA targeting a TRAC gene, a gRNA targeting aB2M gene, and a vector comprising a donor template that comprises anucleic acid encoding a CAR, wherein the CAR comprises (i) an ectodomainthat comprises an anti-CD19 antibody fragment, (ii) a CD8 transmembranedomain, and (iii) an endodomain that comprises a CD28 or 41BBco-stimulatory domain and optionally a CD3z co-stimulatory domain,wherein the nucleic acid encoding the CAR is flanked by left and righthomology arms to the TRAC gene locus and (b) producing an engineered Tcell suitable for allogeneic transplantation.

Other aspects of the present disclosure provide methods for producing anengineered T cell suitable for allogenic transplantation, the methodcomprising (a) delivering to a composition comprising a T cell aRNA-guided nuclease, a gRNA targeting a TRAC gene, a gRNA targeting aB2M gene, and a vector comprising a donor template that comprises anucleic acid encoding a CAR, wherein the CAR comprises (i) an ectodomainthat comprises an anti-CD70 antibody fragment, (ii) a CD8 transmembranedomain, and (iii) an endodomain that comprises a CD28 or 41BBco-stimulatory domain and optionally a CD3z co-stimulatory domain,wherein the nucleic acid encoding the CAR is flanked by left and righthomology arms to the TRAC gene locus and (b) producing an engineered Tcell suitable for allogeneic transplantation.

Yet other aspects of the present disclosure provide methods forproducing an engineered T cell suitable for allogenic transplantation,the method comprising (a) delivering to a composition comprising a Tcell a RNA-guided nuclease, a gRNA targeting a TRAC gene, a gRNAtargeting a B2M gene, and a vector comprising a donor template thatcomprises a nucleic acid encoding a CAR, wherein the CAR comprises (i)an ectodomain that comprises an anti-BCMA antibody fragment, (ii) a CD8transmembrane domain, and (iii) an endodomain that comprises a CD28 or41BB co-stimulatory domain and optionally a CD3z co-stimulatory domain,wherein the nucleic acid encoding the CAR is flanked by left and righthomology arms to the TRAC gene locus and (b) producing an engineered Tcell suitable for allogeneic transplantation.

In some embodiments, the engineered T cells are unpurified and/orunenriched. In some embodiments, the population of cells is unpurifiedand/or unenriched.

In some embodiments, the anti-CD19 antibody fragment is an anti-CD19scFv antibody fragment. In some embodiments, the anti-CD70 antibodyfragment is an anti-CD70 scFv antibody fragment. In some embodiments,the anti-BCMA antibody fragment is an anti-BCMA scFv antibody fragment.

In some embodiments, the antibody fragment (e.g., scFv fragment) ishumanized. In some embodiments, the humanized anti-CD19 antibodyfragment is encoded by the nucleotide sequence of SEQ ID NO: 1333 and/orwherein the humanized anti-CD19 antibody fragment comprises the aminoacid sequence of SEQ ID NO: 1334. In some embodiments, the humanizedanti-CD19 antibody fragment comprises a heavy chain that comprises theamino acid sequence of SEQ ID NO: 1595. In some embodiments, thehumanized anti-CD19 antibody fragment comprises a light chain thatcomprises the amino acid sequence of SEQ ID NO: 1596. In someembodiments, the humanized anti-CD70 antibody fragment is encoded by thenucleotide sequence of SEQ ID NO: 1475 or 1476 and/or wherein thehumanized anti-CD70 antibody fragment comprises the amino acid sequenceof SEQ ID NO: 1499 or 1500. In some embodiments, the humanized anti-CD70antibody fragment comprises a heavy chain that comprises the amino acidsequence of SEQ ID NO: 1592. In some embodiments, the humanizedanti-CD70 antibody fragment comprises a light chain that comprises theamino acid sequence of SEQ ID NO: 1593. In some embodiments, thehumanized anti-BCMA antibody fragment is encoded by the nucleotidesequence of SEQ ID NO: 1479 or 1485 the humanized anti-BCMA antibodyfragment comprises the amino acid sequence of SEQ ID NO: 1503 or 1509.In some embodiments, the humanized anti-BCMA antibody fragment comprisesa heavy chain that comprises the amino acid sequence of SEQ ID NO: 1589or 1524. In some embodiments, the humanized anti-BCMA antibody fragmentcomprises a light chain that comprises the amino acid sequence of SEQ IDNO: 1590 or 1526.

In some embodiments, the ectodomain of the CAR further comprises asignal peptide, optionally a CD8 signal peptide. In some embodiments,the CAR further comprises a hinge domain, optionally a CD8 hinge domain,located between the anti-CD19 antibody fragment and the CD8transmembrane domain. In some embodiments, the CAR comprises thefollowing structural arrangement from N-terminus to C-terminus: theectodomain that comprises an anti-CD19 antibody fragment, a CD8 hingedomain, the CD8 transmembrane domain, and the endodomain that comprisesa CD28 or 41BB co-stimulatory domain and a CD3z co-stimulatory domain.

In some embodiments, the CAR (anti-CD19 CAR) is encoded by thenucleotide sequence of SEQ ID NO: 1316 and/or wherein the CAR comprisesthe amino acid sequence of SEQ ID NO: 1338. In some embodiments, the CAR(anti-CD70 CAR) is encoded by the nucleotide sequence of SEQ ID NO:1423, 1424, or 1275, and/or wherein the CAR comprises the amino acidsequence of SEQ ID NO: 1449, 1450, or 1276. In some embodiments, the CAR(anti-BCMA CAR) is encoded by the nucleotide sequence of SEQ ID NO:1427, 1428, 1434, or 1435, and/or wherein the CAR comprises the aminoacid sequence of SEQ ID NO: 1453, 1454, 1460, or 1461.

In some embodiments, at least 70% (e.g., at least 75%, at least 80%, atleast 85%, at least 90%, or at least 95%) of the engineered T cells donot express a detectable level of TCR and/or B2M surface protein.

In some embodiments, at least 50% (e.g., at least 55%, at least 60%, atleast 65%, at least 70%, or at least 75%) of the engineered T cellsexpress a detectable level of the CAR.

In some embodiments, at least 50% (e.g., at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, or at least 80%) of theengineered T cells express a detectable level of the CAR and do notexpress a detectable level of TCR surface protein or B2M surface protein(e.g., detectable by flow cytometry.

In some embodiments, co-culture of the engineered T cell with CD19+ Bcells results in lysis of at least 50% (e.g., at least 55%, at least60%, at least 65%, at least 70%, or at least 75%) of the CD19+ B cells.In some embodiments, co-culture of the engineered T cell with CD70+ Bcells results in lysis of at least 50% (e.g., at least 55%, at least60%, at least 65%, at least 70%, or at least 75%) of the CD70+ B cells.In some embodiments, co-culture of the engineered T cell with BCMA+ Bcells results in lysis of at least 50% (e.g., at least 55%, at least60%, at least 65%, at least 70%, or at least 75%) of the BCMA+ B cells.

In some embodiments, the engineered T cells produce interferon gamma inthe presence of CD19+ cells. In some embodiments, the engineered T cellsproduce interferon gamma in the presence of CD70+ cells. In someembodiments, the engineered T cells produce interferon gamma in thepresence of BCMA+ cells.

In some embodiments, the engineered T cells do not proliferate in theabsence of cytokine stimulation, growth factor stimulation, or antigenstimulation.

In some embodiments, the population of cells further comprises adisrupted programmed cell death protein 1 (PD1) gene. In someembodiments, at least 70% (e.g., at least 75%, at least 80%, at least85%, or at least 90%) of the engineered T cells do not express adetectable level of PD1 surface protein.

In some embodiments, the population of cells further comprises adisrupted cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene. Insome embodiments, at least 70% (e.g., at least 75%, at least 80%, atleast 85%, or at least 90%) of the engineered T cells do not express adetectable level of CTLA-4 surface protein.

In some embodiments, the population of cells further comprises a gRNAtargeting the TRAC gene, a gRNA targeting the B2M gene, and Cas9 protein(e.g., a S. pyogenes Cas9 protein).

In some embodiments, the gRNA targeting the TRAC gene comprises thenucleotide sequence of any one of SEQ ID NOs: 83-158. In someembodiments, the gRNA targeting the TRAC gene targets the nucleotidesequence of any one of SEQ ID NOs: 7-82. In some embodiments, the gRNAtargeting the B2M gene comprises the nucleotide sequence of any one SEQID NOs: 458-506. In some embodiments, the gRNA targeting the B2M genetargets the nucleotide sequence of any one of SEQ ID NOs: 409-457. Insome embodiments, the gRNA targeting the TRAC gene comprises thenucleotide sequence of SEQ ID NO: 152. In some embodiments, the gRNAtargeting the TRAC gene targets the nucleotide sequence of SEQ ID NO:76. In some embodiments, the gRNA targeting the B2M gene comprises thenucleotide sequence of SEQ ID NO: 466. In some embodiments, the gRNAtargeting the B2M gene targets the nucleotide sequence of SEQ ID NO:417.

In some embodiments, the population of cells further comprises a gRNAtargeting the PD1 gene. In some embodiments, the gRNA targeting the PD1gene comprises the nucleotide sequence of any one of SEQ ID NOs:1083-1274 and/or targets the nucleotide sequence of any one of SEQ IDNOs: 891-1082. In some embodiments, the gRNA targeting the PD1 genecomprises the nucleotide sequence of SEQ ID NOs: 1086. In someembodiments, the gRNA targeting the PD1 gene targets the nucleotidesequence of SEQ ID NO: 894.

In some embodiments, the population of cells further comprises a gRNAtargeting the CTLA-4 gene. In some embodiments, the gRNA targeting theCTLA-4 gene comprises the nucleotide sequence of any one of SEQ ID NOs:1289-1298. In some embodiments, the gRNA targeting the CTLA-4 genetargets the nucleotide sequence of any one of SEQ ID NOs: 1278-1287. Insome embodiments, the gRNA targeting the CTLA-4 gene comprises thenucleotide sequence of SEQ ID NO: 1292. In some embodiments, the gRNAtargeting the CTLA-4 gene targets the nucleotide sequence of SEQ ID NO:1281.

In some embodiments, engineered T cells of the population of cellscomprise a deletion of the nucleotide sequence of SEQ ID NO: 76,relative to unmodified T cells.

In some embodiments, the disrupted B2M gene comprises an insertion of atleast one nucleotide base pair and/or a deletion of at least onenucleotide base pair.

In some embodiments, a disrupted B2M gene of the engineered T cellscomprises at least one nucleotide sequence selected from the groupconsisting of: SEQ ID NO: 1560; SEQ ID NO: 1561; SEQ ID NO: 1562; SEQ IDNO: 1563; SEQ ID NO: 1564; and SEQ ID NO: 1565.

In some embodiments, at least 16% of the cells comprise a B2M geneedited to comprise the nucleotide of SEQ ID NO: 1560; at least 6% of thecells comprise a B2M gene edited to comprise the nucleotide of SEQ IDNO: 1561; at least 4% of the cells comprise a B2M gene edited tocomprise the nucleotide of SEQ ID NO: 1562; at least 2% of the cellscomprise a B2M gene edited to comprise the nucleotide of SEQ ID NO:1563; at least 2% of the cells comprise a B2M gene edited to comprisethe nucleotide of SEQ ID NO: 1564; and at least 2% of the cells comprisea B2M gene edited to comprise the nucleotide of SEQ ID NO: 1565.

In some embodiments, the vector is an adeno-associated viral (AAV)vector. In some embodiments, the AAV vector is an AAV serotype 6 (AAV6)vector. In some embodiments, the AAV vector comprise the nucleotidesequence of any one of SEQ ID NOs: 1354-1357. In some embodiments, theAAV vector comprise the nucleotide sequence of SEQ ID NO: 1354. In someembodiments, the AAV vector comprise the nucleotide sequence of any oneof SEQ ID NOs: 1358-1360. In some embodiments, the AAV vector comprisethe nucleotide sequence of SEQ ID NO: 1360. In some embodiments, the AAVvector comprise the nucleotide sequence of any one of SEQ ID NOs: 1365,1366, 1372, or 1373. In some embodiments, the AAV vector comprise thenucleotide sequence of SEQ ID NOs: 1366 or 1373.

In some embodiments, the donor template comprises the nucleotidesequence of any one of SEQ ID NOs: 1390-1393. In some embodiments, thedonor template comprises the nucleotide sequence of SEQ ID NO: 1390. Insome embodiments, the donor template comprises the nucleotide sequenceof any one of SEQ ID NOs: 1394-1396. In some embodiments, the donortemplate comprises the nucleotide sequence of SEQ ID NO: 1396. In someembodiments, the donor template comprises the nucleotide sequence of anyone of SEQ ID NOs: 1401, 1402, 1408, or 1409. In some embodiments, thedonor template comprises the nucleotide sequence of SEQ ID NO: 1402 or1409. It is understood that the inventions described in thisspecification are not limited to the examples summarized in thisSummary. Various other aspects are described and exemplified herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of materials and methods for producing genome-editedcells engineered to express a chimeric antigen receptor (CAR) constructon the cell surface, and materials and methods for treating a patientusing the genome-edited engineered cells disclosed and described in thisspecification can be better understood by reference to the accompanyingfigures, in which:

FIG. 1 is a graph depicting a rank ordered list of IVT gRNAs targetingthe TRAC gene and their respective activities (% InDel) in 293 cells.

FIGS. 2A and 2B are a series of graphs depicting a rank ordered list ofIVT gRNAs targeting the CD3-epsilon (CD3E) gene and their respectiveactivities (% InDel) in 293 cells.

FIG. 3 is a graph depicting a rank ordered list of IVT gRNAs targetingthe B2M gene and their respective activities (% InDel) in 293 cells.

FIGS. 4A, 4B, 4C, and 4D are a series of graphs depicting a rank orderedlist of IVT gRNAs targeting the CIITA gene and their respectiveactivities (% InDel) in 293 cells.

FIGS. 5A, 5B, and 5C are a series of graphs depicting a rank orderedlist of IVT gRNAs targeting the PD1 gene and their respective activities(% InDel) in 293 cells.

FIGS. 6A and 6B are a series of images of flow cytometry plots depictinglack of reactivity to PHA-L, but normal responses to PMA/ionomycin byTCRa or CD3ε null human T cells as compared to controls. FIG. 6A showslevels of the T cell activation marker CD69 (top panel) and levels ofCFSE (marking proliferative history) (bottom panel), and FIG. 6B depictslevels of degranulation (CD107a) and IFNg 1 (left panel) and depictslevels of IL-2 and TNF (right panel) in control and gene edited human Tcells.

FIG. 7 is a series of graphs depicting the loss of MHC-II surfaceexpression measured by flow cytometry after treatment of primary human Tcells with RNPs containing RNPs to the CIITA or RFX-5 genes.

FIG. 8 is a graph depicting levels of surface protein loss as measuredby flow cytometry after treatment of primary human T cells with RNPstargeting either 1, 2 or 3 genes alone or simultaneously (multiplexediting).

FIG. 9 is a graph depicting surface levels of PD1 by flow cytometryafter PMA/ionomycin treatment in control and RNP (containing PD1 sgRNA)containing primary human T cells.

FIG. 10 is an image generated from an Agilent Tapestation analysis ofDNA amplified by PCR from cells that had undergone homology directedrepair of a DNA double stranded break evoked by Cas9/sgRNA RNP complextargeting a genomic site in the AAVS1 locus. The repair was facilitatedby a donor template containing a GFP expression cassette flanked byhomology arms around the RNP cut site and was delivered by an AAV6virus. No RNP control and an RNP targeting a different genomic locuswith no homology to the AAV donor template are also shown.

FIG. 11 shows flow cytometry plots depicting single T cells withconcurrent loss of TCRa and B2M and expression of GFP after induction ofHDR by a distinct RNP targeting the AAVS1 locus and AAV6 delivered donortemplate in primary human T cells.

FIG. 12 is a graph quantifying the percentage of cells that are GFPpositive (a readout for RNP/AAV HDR) in cells from 3 biological donorstreated with controls as well as RNPs targeting AAVS1, TRAC and B2M. HDRis also quantified in gates of cells that were rendered TRAC⁻B2M⁺ orTRAC⁻B2M⁻ by Cas9/sgRNAs.

FIG. 13A is a graphical depiction of an allogeneic CAR−T cell in whichexpression of one more gene is modulated by CRISPR/Cas9/sgRNAs and AAV6delivered donor templates. This depiction shows modulation of one ormore target genes with knock-in of a CAR construct within or near thetarget gene locus as mediated by HDR.

FIG. 13B is a graphical depiction of an allogeneic CAR−T cell that lacksMHC-I expression produced by CRISPR/Cas9/sgRNAs and AAV6 delivered donortemplates. This depiction shows knockout of the TRAC gene with knock-inof a CAR construct into the TRAC locus (mediated by HDR). This depictionalso shows deletion of sites in the B2M gene.

FIG. 14 is a schematic representation of model graphics of AAVconstructs to be used in production of AAV virus for delivery of donorDNA templates for repair of Cas9 induced double stranded breaks andsite-specific transgene insertion.

FIG. 15 is a graph depicting TIDE analysis on DNA from Cas9:sgRNA RNPtreated human T cells to demonstrate concurrent triple knockout of theTCR, B2M and CIITA. The RNP treatments included combinations of TCRa(TRAC), B2M and/or CIITA.

FIG. 16A is a series of graphs depicting the ability of T cellsexpressing an anti-CD19 CAR construct inserted into the AAVS1 locus(AAVS1 RNP+CTX131) or the TRAC locus (TRAC RNP+CTX-138) to lyse the Rajilymphoma cells in a co-culture assay (Left panel) and to produceInterferon gamma (IFNg or IFNγ) in the presence of Raji lymphoma cells(right panel).

FIG. 16B is a series of graphs demonstrating a lack of interferon gamma(IFNg) production in the presence of anti-CD19 CAR−T cells generated byCRISPR/AAV co-cultured with K562 cells (left panel). IFNg productionlevels increase in the presence of CAR−T expressing anti-CD19 CAR fromeither the AAVS1 locus (AAVS1 RNP+CTX131) or the TRAC locus (TRACRNP+CTX-138) when co-cultured with K562 cells that have been designed tooverexpress CD19 (right panel).

FIG. 17A is a series of flow cytometry plots demonstrating that singlecells express a CAR construct and lack surface expression of the TCR andB2M only when the cells have been treated with RNPs to TRAC and B2M andhave been infected with a vector that delivers a donor templatecontaining a CAR construct flanked by homologous sequence to the TRAClocus mediated site specific integration and expression of the CARconstruct.

FIG. 17B is a series flow cytometry plots demonstrating normalproportions of CD4 and CD8 T cells that are CAR⁺TCR⁻B2M⁻.

FIG. 17C is a dot plot summarizing the proportions of CD4 and CD8expression in replicates of the flow cytometry experiment in FIG. 17B.Four replicates of CAR⁺TCR⁻B2M⁻ and four Control replicates wereanalyzed. CD4 and CD8 frequencies remain unchanged in the production ofCAR⁺TCR⁻B2M⁻ T cells compared to controls.

FIG. 17D is a graph depicting the number of viable cells enumerated 8days post electroporation and AAV6 infection.

FIG. 18A is a graph demonstrating lack of IFNg production in co-culturesof K562 and the indicated cells.

FIG. 18B is a graph demonstrating increased production of IFNg only incells made to express an anti-CD19 CAR integrated in the TRAC locus withor without knockout of B2M when T cells were co-cultured withCD19-expressing K562 cells.

FIG. 18C is a graph demonstrating increased IFNg production inco-cultures of CD19+ Raji lymphoma cell line and T cells treated asindicated.

FIG. 19 is a graph depicting a statistically significant decrease intumor volume (mm³) (p=0.007) in NOG Raji mice following treatment withTC1 cells.

FIG. 20 is a survival curve graph demonstrating increased survival ofNOG Raji mice treated with TC1 cells in comparison to NOG Raji micereceiving no treatment.

FIG. 21A is a series of flow cytometry plots demonstrating that TC1cells persist in NOG Raji mice.

FIG. 21B is a graph demonstrating that TC1 cells selectively eradicatesplenic Raji cells in NOG Raji mice treated with TC1 in comparison tocontrols (NOG Raji mice with no treatment or NOG mice). The effect isdepicted as a decreased splenic mass in NOG Raji mice treated with TC1in comparison to controls.

FIG. 22 is a series of flow cytometry plots demonstrating thatpersistent splenic TC1 cells are edited in two independent NOG Raji micewith TC1 treatment.

FIG. 23 is a graph demonstrating that TC1 cells do not exhibit cytokineindependent growth in vitro.

FIG. 24A is a graphical depiction of a CAR−T cell that lacks MHC-Iexpression produced by CRISPR/Cas9/sgRNAs and AAV6 delivered donortemplates. This depiction shows knockout of the TRAC gene with knock-inof a CAR construct into the TRAC locus (mediated by HDR). This depictionalso shows deletion of sites in the B2M gene.

FIG. 24B is a schematic representation of AAV constructs used inproduction of AAV virus for delivery of donor DNA templates for repairof Cas9 induced double stranded breaks and site-specific transgeneinsertion.

FIG. 25A is flow cytometry data demonstrating the production ofTRAC⁻CD70CAR+ T cells using TRAC sgRNA containing RNPs and AAV6 todeliver the CTX-145 donor template into T cells.

FIG. 25B shows the maintenance of CD4/CD8 subset proportions inTRAC⁻CD70CAR+ T cells generated using TRAC sgRNA containing RNPs andAAV6 to deliver the CTX-145 donor template into T cells.

FIG. 26 is flow cytometry data demonstrating expression of the CD70CARconstruct only when there is RNP to induce a double stranded break atthe TRAC locus. Expression of the CD70 CAR construct does not occur withepisomal AAV6 vector.

FIG. 27 is flow cytometry data showing the production of CD70CAR−T withTCR and B2M deletions.

FIG. 28A is a histogram from flow cytometry data showing increasedexpression of CD70 from K562−CD70 cells that were subsequently used in afunctional assay.

FIG. 28B is a graph showing native CD70 expression levels in a panel ofcell lines. The data is normalized to CD70 expression in Raji cells.

FIG. 29A is a graph showing % cell lysis of CD70 expressing K562 cells(CD70-K562) in the presence of TRAC⁻/anti-CD70 CAR+ T cells (left panel)and IFNγ secretion from TRAC⁻/anti-CD70 CAR+ T cells only when theyinteract with CD70 expressing K562 cells (CD70−K562) (right panel).

FIG. 29B is a graph depicting IFNγ secretion from TRAC⁻/anti-CD70 CAR+ Tcells (TRAC−CD70CAR+) only when co-cultured with CD70+ Raji cells, andnot in the CD70 negative Nalm6 cells.

FIG. 29C is a graph showing that TRAC⁻/anti-CD70 CAR+ T cells(TRAC−CD70CAR+) do not secrete IFNγ due to “self” stimulation when onlyTRAC⁻/anti-CD70 CAR+ T cells are present alone in the absence of CD70expressing target cells.

FIG. 29D is flow cytometry data demonstrating GranzymeB activity only inthe CD70+ expressing target cells (Raji) that interacted withTRAC⁻/anti-CD70 CAR+ T cells (TCR−CAR+).

FIG. 30A is a graph of cell killing data demonstrating CD70 specificcell killing.

FIG. 30B is a graph that shows TRAC−CD70CAR+ T cells induce cell lysisof renal cell carcinoma derived cell lines (24 hour and 48 hour timepoints).

FIG. 30C is a graph demonstrating that TCR− deficient anti-CD70 CAR−Tcells (CD70 CAR+) display cell killing activity against a panel of RCCcell lines with varying CD70 expression (24 hour time point), ascompared to TCR− cells (control).

FIG. 31A is a graphical depiction of a CAR−T cell that lacks MHC-Iexpression produced by CRISPR/Cas9/sgRNAs and AAV6 delivered donortemplates. This depiction shows knockout of the TRAC gene with knock-inof a CAR construct into the TRAC locus (mediated by HDR). This depictionalso shows deletion of sites in the B2M gene.

FIG. 31B is a schematic representation of AAV constructs used inproduction of AAV virus for delivery of donor DNA templates for repairof Cas9 induced double stranded breaks and site-specific transgeneinsertion. Schematic design of the anti-BCMA CAR AAV donor template.Both CTX152 and CTX154 were designed to co-express the CAR and Greenfluorescent protein (GFP) from a bicistronic mRNA. CTX-152 CAR=VH−VL;CTX-154 CAR=VL−VH.

FIG. 32 is flow cytometry data showing the production of anti-BCMA(CTX152 and CTX154) CAR−T cells with TCR and B2M deletions(TRAC−/B2M−BCMA CAR+ Cells). TRAC and B2M genes were disrupted usingCRISPR/CAS9 and the CAR constructs were inserted into the TRAC locususing homologous directed repair. Approximately 77% of the T-Cells wereTCR−/B2M− as measured by FACS (top panel). CAR+ cells were both positivefor GFP expression and recombinant BCMA binding (bottom panel). TheseCAR T− Cells were produced according to the methods described in Example15. x and y axes are depicted in logarithmic scale.

FIG. 33A is a graph showing that treatment of RPMI8226 cells thatexpress BCMA with TRAC−B2M− BCMA CAR−T cells results in cytotoxicity,whereas treatment with unmodified T-Cells (NO RNP/AAV) shows minimalcytotoxicity.

FIG. 33B is a graph showing high levels of IFNγ secretion from anti-BCMACAR−T cells and minimal secretion from unmodified T-Cells (NO RNP/AAV).Both plots are from the same cytotoxicity experiment. Interferon gammawas measured according to the method described in Example 18.

FIG. 34 is a graph showing a strong correlation between surface CD19 CARexpression and HDR frequency (R²=0.88). This indicates site specificintegration and high expression levels of CD19 CAR construct into theTRAC locus of T cells using CRISPR gene editing.

FIG. 35A is flow cytometry data demonstrating GranzymeB activity only inthe CD19+ expressing target cells (Nalm6) that interacted withTRAC−/B2M−CD19CAR+ T cells.

FIG. 35B is a graph showing that TRAC−/B2M−CD19CAR+ T cells secrete highlevels of IFNγ when cultured with CD19 positive Nalm6 cells.

FIG. 35C is a graph of cell killing data showing that TRAC−/B2M−CD19CAR+T cells selectively kills Nalm6 cells at low T cell to target cellratios.

FIG. 36A are a series of flow cytometry graphs showing the percentage ofcells expressing CD70 during the production of CD70 CAR+ T-cells.

FIG. 36B are a series of flow cytometry graphs depicting proportions ofT cells that express one or more of CD4, CD8, TCR or CD70 CAR. The toppanel of plots correspond to CD70− population of cells from FIG. 36A.The bottom panel of plots correspond to CD70+ population of cells fromFIG. 36A.

FIG. 37A is a graph depicting a decrease in tumor volume (mm³) at day 31following treatment of NOG mice that were injected subcutaneously withA498 renal cell carcinoma cell lines with TRAC−/anti-CD70 CAR+ T cells.All Groups of NOG mice were injected with 5×10⁶ cells/mouse. Group 1received no T cell treatment. Mice in Group 2 were treated intravenouslywith 1×10⁷ cell/mouse of TRAC−/anti-CD70 CAR+ T cells on day 10. Mice inGroup 3 were treated intravenously with 2×10⁷ cell/mouse ofTRAC−/anti-CD70 CAR+ T cells on day 10.

FIG. 37B is a graph depicting a decrease in tumor volume (mm³) followingtreatment of NOG mice that were injected subcutaneously with A498 renalcell carcinoma cell lines with TRAC−/anti-CD70 CAR+ T cells. Both Groupsof NOG mice were injected with 5×10⁶ cells/mouse. The control groupreceived no T cell treatment, and the test group of mice were treatedintravenously with 2×10⁷ cell/mouse of TRAC−/anti-CD70 CAR+ T cells onday 10.

FIG. 38A is a series of flow cytometry plots demonstrating theproduction of anti CD19 CAR−T cells expressing the CAR and lackingsurface expression of TCR and B2M, which either have low or absentsurface expression of PD1 (PD1^(LO) and PD1^(KO), respectively).Preferred anti-CD19 CAR−T cells express the CAR and lack surfaceexpression of TCR, B2M and PD1.

FIG. 38B is a bar graph depicting the editing efficiency for each geneedit as measured by flow cytometry. Measurements were taken from thecell population depicted in the bottom row of FIG. 38A.

FIG. 39 is a graph depicting high editing rates achieved at the TRAC andB2M loci in TRAC⁻/B2M⁻CD19CAR+ T cells (TC1). Surface expression of TCRand MHCI, which is the functional output of gene editing, was measuredand plotted as editing percentage on the y-axis. High efficiency (e.g.,greater than 50%) site-specific integration and expression of the CARfrom the TRAC locus were detected. These data demonstrate greater than50% efficiency for the generation of TRAC⁻/B2M⁻/anti-CD19CAR+ T cells.

FIG. 40 is a series of flow cytometry plots of human primary T-cells,TRAC⁻/B2M⁻CD19CAR+ T cells (TC1), 8 days post-editing. The graphs showreduced surface expression of TRAC and B2M. TCR/MHC I double knockoutcells express high levels of the CAR transgene (bottom panel). Negativeselection of TC1 cells with purification beads leads to a reduction inTCR positive cells (right panel).

FIG. 41 is a graph demonstrating a statistically significant increase inproduction of IFNγ in TRAC⁻/B2M⁻CD19CAR+ T cells (TC1) when co-culturedwith CD19-expressing K562 cells but not when co-cultured with K562 cellsthat lack the expression of CD19. This experiment was performed intriplicate according to the method in FIG. 18B. Statistical analysis wasperformed with ANOVA using Tukey's multiple comparisons test.

FIGS. 42A and 42B are survival curve graphs demonstrating increasedsurvival of NOG Raji mice (FIG. 42A) or NOG Nalm6 mice (FIG. 42B)treated with TRAC−/B2M− CD19CAR+ T cells (TC1) on Day 4, in comparisonto control mice receiving no treatment on Day 1. This was, in part, amodified replicate experiment of FIG. 20.

FIG. 43 is a graph showing cell lysis data following treatment of Nalm6tumor cells with TRAC−/B2M−CD19CAR+ T cells (TC1) or with the CAR−Tdonor DNA template packaged in a lentivirus vector. Both treatmentsyielded similar potency with respect to percent cell lysis. ControlTCR⁻CAR⁻ T cells measured in separate experiment showed no cell lysisactivity.

FIG. 44 is a dot plot depicting the consistent percentage ofTRAC⁻/B2M⁻CD19CAR+ T cells (TC1) that are produced from the donor DNAtemplate. Additionally, in combination with the additional attributesof >80% TCR−/B2M− double knock out and >99.6% TCR− followingpurification, TC1 production is more homogenous and consistent thanother lentiviral CAR−T products.

FIG. 45A is a graph showing that treatment of RPMI8226 which expressBCMA, causes high levels of IFNγ secretion from TRAC−B2M− BCMA CAR−Tcells and minimal secretion from unmodified T-Cells (TCR+CAR−) (4:1 Tcell:RPMI-8226 ratio). Interferon gamma was measured according to themethod described in Example 18.

FIG. 45B is a graph showing that treatment of RPMI8226 cells whichexpress BCMA, with TRAC−/B2M− BCMA CAR+ T cells results in cell lysisand cytotoxicity.

FIGS. 46A-46C are graphs of data demonstrating that anti-BCMA CAR−Tcells show specific cytotoxicity towards BCMA expressing U-266 andRPMI8226 cells. Allogeneic T-Cells (TRAC−, B2M−) that expressed theCTX152 and CTX154 anti-BCMA CAR constructs express INFγ in the presenceand induced lysis of U-266 (FIG. 46A) and RMPI8226 (FIG. 46B) cellswhile allogeneic T cells lacking the CAR and unmodified T-Cells showedminimal activity. CTX152 and CTX154 showed no specific cytotoxicitytowards K562 cells that lacks BCMA expression (FIG. 46C).

FIGS. 47A-47B are graphs of data demonstrating that other anti-BCMA CART cells secret interferon gamma specifically in the presence of cellsexpressing BCMA.

FIG. 48 is a graph showing anti-BCMA CAR expression. Allogeneic CAR Tcells were generated as previously described. Anti-BCMA CAR expressionwas measured by determining the percent of cells that bound biotinylatedrecombinant human BCMA subsequently detected by FACS usingstreptavidin-APC.

FIGS. 49A-49C are graphs of data demonstrating that anti-BCMA CAR Tcells expressing the CAR are potently cytotoxic towards RPMI-8226 cells.CAR constructs were evaluated for their ability to kill RPMI-8226 cells.All CAR T cells were potently cytotoxic towards effector cells whileallogeneic T cells lacking a CAR showed little cytotoxicity.

FIG. 50 shows flow cytometry plots demonstrating that the health ofTRAC−/B2M−/anti-CD19+CAR T cells is maintained at day 21 post geneediting. Cells were assayed for low exhaustion markers, LAGS and PD1(left graph), as well as low senescence marker, CD57 (right graph).

FIG. 51 shows flow cytometry graphs demonstrating that 95.5% of the geneedited cells are TCR negative, without further enrichment for a TCRnegative cell population. Following enrichment/purification, greaterthan 99.5% of the gene edited cells are TCR negative.

FIG. 52A shows a representative FACS plot of β2M and TRAC expression oneweek following gene editing (left) and a representative FACS plot of CARexpression following knock-in to the TRAC locus (right). FIG. 52B is agraph showing decreased surface expression of both TCR and MHC-Iobserved following gene editing. Combined with a high CAR expression,this leads to more than 60% cells with all desired modifications(TCR−/β2M−/CAR+). FIG. 52C is a graph showing that production ofallogeneic anti-BCMA CAR− T cells preserves CD4 and CD8 proportions.

FIG. 53 is a graph showing that allogenic BCMA−CAR−T cells maintaindependency on cytokines for ex vivo expansion.

FIG. 54A shows graphs demonstrating that allogeneic anti-BCMA CAR−Tcells efficiently and selectively kill the BCMA-expressing MM cell lineMM.1S in a 4-hour cell kill assay, while sparing the BCMA-negativeleukemic line K562. FIG. MB is a graph showing that the cells alsoselectively secrete the T cell activation cytokines IFNγ and IL-2, whichare upregulated in response to induction only by MM.1S cells. Valuesbelow the limit of detection are shown as hollow data points. Potentcell kill was also observed upon exposure of anti-BCMA CAR−T cells toadditional MM cell lines: (FIG. 54C) RPMI-8226 (24-hour assay) and (FIG.54 D) H929 (4-hour assay).

FIG. 55 is a graph showing that allogeneic anti-BCMA CAR−T cellseradicate tumors in a subcutaneous RPMI-8226 tumor xenograft model.1×107 RPMI-8226 cells were injected subcutaneously into NOG mice,followed by CAR−T cells intravenously 10 days after inoculation. Noclinical signs of GvHD were observed in the mice at any timepoint. N=5for each group.

FIG. 56A is a graph demonstrating that high editing rates are achievedat the TRAC and β2M loci resulting in decreased surface expression ofTCR and MHC-I. Highly efficient site-specific integration and expressionof the CAR from the TRAC locus was also detected. Data are from threehealthy donors.

FIG. 56B is a graph demonstrating that production of allogeneicanti-CD70 CAR−T cells (TCR−β2M−CAR+) preserves CD4 and CD8 proportions.

FIG. 57 is a graph demonstrating that allogeneic anti-CD70 CAR−T cells(TCR−β2M− CAR+) show potent cytotoxicity against the CD70+ MM.1Smultiple myeloma-derived cell line.

FIG. 58A is a graph showing that multi-editing results in decreasedsurface expression of TCR and MHC-I, as well as high CAR expression.FIG. 58B is a graph showing that CD4/CD8 ratios remain similar inmulti-edited anti-BCMA CAR−T cells. FIG. 58C is a graph showing thatmulti-edited anti-BCMA CAR−T cells remain dependent on cytokines forgrowth following multi CRISPR/Cas9 editing.

FIG. 59A are graphs showing that anti-BCMA CAR−T cells efficiently andselectively kill the BCMA-expressing MM cell line MM.1S in a 4-hour cellkill assay, while sparing the BCMA-negative leukemic line K562. FIG. 59Bare graphs showing that the cells also selectively secrete the T cellactivation cytokines IFNγ and IL-2, which are upregulated in response toinduction only by BCMA+ MM.1S cells.

FIG. 60 is a graph showing no observed change in Lag3 exhaustion markerbetween double or triple knockout (KO) anti-BCMA CAR−T cells after 1week in culture. However, following 4 weeks in culture, Lag3 exhaustionmarker expression was reduced in the triple KO anti-BCMA CAR−T cells.

FIG. 61 is a schematic of CTX-145b (SEQ ID NO: 1360), which includes ananti-CD70 CAR having a 4-1BB co-stimulatory domain flanked by left andright homology arms to the TRAC gene.

FIG. 62 is a graph showing that normal proportions of CD4+/CD8+ T cellsubsets maintain the TRAC−/B2M−/anti-CD70 CAR+ fraction from cellstreated with TRAC and B2M sgRNA-containing RNPs and CTX 145b AAV6.

FIG. 63 are graphs demonstrating efficient transgene insertion andconcurrent gene knockout by Cas9:sgRNA RNP and AAV6 delivered donortemplate (CTX-145 and CTX-145b) containing an anti-CD70 CAR construct inprimary human T cells.

FIG. 64 is a graph demonstrating that normal proportions of CD4+/CD8+ Tcell subsets are maintained in the PD1−/TRAC−/B2M−/anti-CD70 CAR+fraction from cells treated with PD1, TRAC and B2M sgRNA-containing RNPsand CTX-145b AAV6.

FIG. 65 is a graph showing that TRAC−/B2M−/anti-CD70 CAR+ cellsdemonstrated potent cell killing of renal cell carcinoma derived celllines (A498 cells) after 24 hours co-incubation.

FIG. 66 is a graph showing that TRAC−/B2M−/anti-CD70 CAR+ cells andPD1−/TRAC−/B2M−/anti-CD70 CAR+ cells induced potent cell killing of CD70expressing adherent renal cell carcinoma (RRC) derived cell line, ACHN,with a CD28 or 41BB costimulatory domain, at a 3:1 ratio T cell:targetcell.

FIG. 67 is a graph showing anti-BCMA (CD28 v. 4-1BB) CAR expression inedited T cells.

FIG. 68 is a graph showing results from a cytotoxicity assay with MM.1Scells and TRAC−/B2M−/anti-BCMA (CD28 or 4-1BB) CAR+ T cells.

FIG. 69 includes graphs showing results from an IFN-γ secretion studywith MM.1S cells (left) or K562 cells (right) and TRAC−/B2M−/anti-BCMA(CD28 or 4-1BB) CAR+ T cells.

FIG. 70 includes graphs showing results from a cell kill assay usingTRAC−/B2M−/anti-BCMA (4-1BB) CAR+ T cells with RPMI-8226 cells (topleft), H929 cells (top right), U2661 cells (bottom left), or K562 cells(bottom right).

FIG. 71 includes graphs showing IFN-γ stimulation studies in thepresence of TRAC−/B2M−/anti-BCMA (4-1BB) CAR+ T cells with RPMI-8226cells (top left), U2261 cells (top right), H929 cells (bottom left), orK562 cells (bottom right).

FIG. 72 includes graphs showing IL-2 stimulation studies in the presenceof TRAC−/B2M−/anti-BCMA (4-1BB) CAR+ T cells with RPMI-8226 cells (topleft), U2261 cells (top right), H929 cells (bottom left), or K562 cells(bottom right).

FIG. 73 includes graphs showing tumor volume in a RPMI-8226 subcutaneoustumor mouse model administered TRAC−/B2M−/anti-BCMA (CD28) CAR+ T cellsor TRAC−/B2M−/PD-1−/anti-BCMA (CD28) CAR+ T cells.

FIG. 74 includes graphs showing results from cytotoxicity (left), IFN-γstimulation (middle), and IL-2 stimulation studies withTRAC−/B2M−/anti-BCMA (4-1BB) CAR+ T cells or TRAC−/B2M−/PD-1−/anti-BCMA(4-1BB) CAR+ T cells in the presence of MM.1 S cells or K562 cells.

FIG. 75 includes a graph showing that TRAC−/B2M−/anti-CD70 CAR+ orTRAC−/B2M−/PD1−/anti-CD70 CAR+ T Cells, with a CD28 or a 41BBcostimulatory domain, display anti-tumor activity in a renal cellcarcinoma mouse model.

BRIEF DESCRIPTION OF THE SEQUENCE LISTING

SEQ ID NOs: 1-3 are sgRNA backbone sequences (Table 1).

SEQ ID NOs: 4-6 are homing endonuclease sequences.

SEQ ID NOs: 7-82 are TRAC gene target sequences (Table 4).

SEQ ID NOs: 83-158 are gRNA spacer sequences targeting the TRAC gene(Table 4).

SEQ ID NOs: 159-283 are CD3E gene target sequences (Table 5).

SEQ ID NOs: 384-408 are gRNA spacer sequences targeting the CD3E gene(Table 5).

SEQ ID NOs: 409-457 are B2M gene target sequences (Table 6).

SEQ ID NOs: 458-506 are gRNA spacer sequences targeting the B2M gene(Table 6).

SEQ ID NOs: 507-698 are CIITA gene target sequences (Table 7).

SEQ ID NOs: 699-890 are gRNA spacer sequences targeting the CIITA gene(Table 7).

SEQ ID NOs: 891-1082 are PD1 gene target sequences (Table 8).

SEQ ID NOs: 1083-1274 are gRNA spacer sequences targeting the PD1 gene(Table 8).

SEQ ID NO: 1275 is the nucleotide sequence for the CAR of CTX-145b(Table 36).

SEQ ID NO: 1276 is the amino acid sequence for the CAR of CTX-145b(Table 36).

SEQ ID NOs: 1277-1287 are CTLA-4 gene target sequences (Table 10).

SEQ ID NOs: 1288-1298 are gRNA spacer sequences targeting the CTLA-4gene (Table 10).

SEQ ID NO: 1299 is a TRAC gene target sequence (Table 11).

SEQ ID NO: 1300 is a PD1 gene target sequence (Table 11).

SEQ ID NOs: 1301 and 1302 are AAVS1 target sequences (Table 11).

SEQ ID NOs: 1303 and 1305 are CD52 target sequences (Table 11).

SEQ ID NOs: 1305-1307 are RFX5 target sequences (Table 11).

SEQ ID NO: 1308 is a gRNA spacer sequence targeting the AAVS1 gene.

SEQ ID NOs: 1309-1311 are gRNA spacer sequences targeting the RFX5 gene.

SEQ ID NO: 1312 is a gRNA spacer sequence targeting the CD52 gene.

SEQ ID NOs: 1313-1338 are donor template component sequences forgenerating the anti-CD19 CAR T cells (see Table 12).

SEQ ID NO: 1339 is the nucleotide sequence for the 4-1BB co-stimulatorydomain.

SEQ ID NO: 1340 is the amino acid sequence for the 4-1BB co-stimulatorydomain.

SEQ ID NO: 1341 is a linker sequence.

SEQ ID NOs: 1342-1347 are chemically-modified and unmodified sgRNAsequences for B2M, TRAC, and AAVS1 (see Table 32).

SEQ ID NOs: 1348-1386 are rAAV sequences of various donor templates (seeTable 34).

SEQ ID NOs: 1387-1422 are left homology arm (LHA) to right homology arm(RHA) sequences of various donor templates (see Table 35).

SEQ ID NOs: 1423-1448 are CAR nucleotide sequences of donor templates ofthe present disclosure (see Table 36).

SEQ ID NOs: 1449-1474 are CAR amino acid sequences encoded by donortemplates of the present disclosure (see Table 37).

SEQ ID NOs: 1475-1498 are scFv nucleic acid sequences of CARs of thepresent disclosure (see Table 38).

SEQ ID NOs: 1499-1522 are scFv amino acid sequences encoded by CARs ofthe present disclosure (see Table 39).

SEQ ID NOs: 1523-1531 are anti-BCMA light chain and heavy chainsequences (see Table 39).

SEQ ID NOs: 1532-1553 are plasmid sequences of the present disclosure.

SEQ ID NOs: 1554-1559 are primer sequences used in a ddPCR assay (seeTable 25).

SEQ ID NOs: 1560-1565 are gene edited sequences in the B2M gene (Table12.3).

SEQ ID NOs: 1566-1573 are gene edited sequences in the TRAC gene (Table12.4).

SEQ ID NOs: 1574 and 1575 are chemically-modified and unmodified sgRNAsequences for PD1 (see Table 32).

SEQ ID NOs: 1576-1577 are ITR sequences (Table 12).

SEQ ID NOs: 1578-1582 are nucleotide sequences for the left homologyarms and right homology arms used for CTX-139.1-CTX-139.3 (Table 12).

SEQ ID NO: 1586 is a CD8 signal peptide sequence (Table 12).

SEQ ID NOs: 1587 and 1588 are chemically-modified and unmodified sgRNAsequences for TRAC (EXON1_T7) (see Table 32).

SEQ ID NOs: 1589-1597 are the heavy chain, light chain and linkersequences for example anti-BCMA, anti-CD70, and anti-CD19 scFv molecules(Table 39).

SEQ ID NO: 1598 is the leader peptide sequence for the anti-CD19 CAR(Table 12).

SEQ ID NO: 1599 is the CD8a transmembrane sequence without the linker(Table 12).

SEQ ID NO: 1600 is the CD8a peptide sequence.

SEQ ID NO: 1601 is the CD28 co-stimulatory domain peptide sequence.

SEQ ID NO: 1602 is the CD3-zeta co-stimulatory domain peptide sequence.

DETAILED DESCRIPTION

Therapeutic Approach

CRISPR edited cells such as, for example, CRISPR edited T cells, canhave therapeutic uses in multiple disease states. By way of non-limitingexample, the nucleic acids, vectors, cells, methods, and other materialsprovided in the present disclosure are useful in treating cancer,inflammatory disease and/or autoimmune disease.

Gene editing provides an important improvement over existing orpotential therapies, such as introduction of target gene expressioncassettes through lentivirus delivery and integration. Gene editing tomodulate gene activity and/or expression has the advantage of precisegenome modification and lower adverse effects, and for restoration ofcorrect expression levels and temporal control.

The materials and methods provided herein are useful in modulating theactivity of a target gene. For example, the target gene can be a genesequence associated with host versus graft response, a gene sequenceassociated with graft versus host response, a gene sequence encoding animmune suppressor (e.g.: checkpoint inhibitor), or any combinationthereof.

The target gene can be a gene sequence associated with a graft versushost response that is selected from the group consisting of TRAC,CD3-epsilon (CD3ε), and combinations thereof. TRAC and CD3ε arecomponents of the T cell receptor (TCR). Disrupting them by gene editingwill take away the ability of the T cells to cause graft versus hostdisease.

The target gene can be a gene sequence associated with a host versusgraft response that is selected from the group consisting of B2M, CIITA,RFX5, and combinations thereof. B2M is a common (invariant) component ofMHC I complexes. Its ablation by gene editing will prevent host versustherapeutic allogeneic T cells responses leading to increased allogeneicT cell persistence. CIITA and RFX5 are components of a transcriptionregulatory complex that is required for the expression of MHC II genes.Disrupting them by gene editing will prevent host versus therapeuticallogeneic T cells responses leading to increased allogeneic T cellpersistence.

The target gene can be a gene sequence encoding a checkpoint inhibitorthat is selected from the group consisting of PD1, CTLA-4, andcombinations thereof. PDCD1 (PD1) and CTLA4 are immune checkpointmolecules that are upregulated in activated T cells and serve to dampenor stop T cell responses. Disrupting them by gene editing could lead tomore persistent and/or potent therapeutic T cell responses.

The target gene can be a sequence associated with pharmacologicalmodulation of a cell. For example, CD52 is the target of thelympho-depleting therapeutic antibody alemtuzumab. Disruption of CD52 bygene editing will make therapeutic T cells resistant to alemtuzumabwhich may be useful in certain cancer settings.

Deletion of the above genes can be achieved with guide RNAs that havechosen from small (<5) to medium scale (>50) screens. The examplesprovided herein further illustrate the selection of various targetregions and gRNAs useful for the creation of indels that result indisruption of a target gene, for example, reduction or elimination ofgene expression and or function. The examples provided herein furtherillustrate the selection of various target regions and gRNAs useful forthe creation of DSBs that facilitate insertion of a donor template intothe genome. Examples of target genes associated with graft versus hostdisease, host versus graph disease and/or immune suppression. In someaspects, the guide RNA is a gRNA comprising a sequence disclosed herein.

The methods use chimeric antigen receptor constructs (CARs) that areinserted into genomic loci by using guide RNA/Cas9 to induce a doublestranded break that is repaired by HDR using an AAV6 delivered donortemplate with homology around the cut site.

A chimeric antigen receptor (CAR) is an artificially constructed hybridprotein or polypeptide containing an antigen binding domain of anantibody (e.g., a single chain variable fragment (scFv)) linked toT-cell signaling or T-cell activation domains. CARs have the ability toredirect T-cell specificity and reactivity toward a selected target in anon-MHC-restricted manner, exploiting the antigen-binding properties ofmonoclonal antibodies. The non-MHC-restricted antigen recognition givesT-cells expressing CARs the ability to recognize an antigen independentof antigen processing, thus bypassing a major mechanism of tumor escape.Moreover, when expressed in T-cells, CARs advantageously do not dimerizewith endogenous T-cell receptor (TCR) alpha and beta chains.

The materials and methods provided herein knock-in a nucleic acidencoding a chimeric antigen receptor (CAR) in or near a locus of atarget gene by permanently deleting at least a portion of the targetgene and inserting a nucleic acid encoding the CAR. The CARs used in thematerials and methods provided herein include (i) an ectodomaincomprising an antigen recognition region; (ii) a transmembrane domain,and (iii) an endodomain comprising at least one costimulatory domain.The nucleic acid encoding the CAR can also include a promoter, one ormore gene regulatory elements, or a combination thereof. For example,the gene regulatory element can be an enhancer sequence, an intronsequence, a polyadenylation (poly(A)) sequence, and/or combinationsthereof.

The donor for insertion by homology directed repair (HDR) contains thecorrected sequence with small or large flanking homology arms to allowfor annealing. HDR is essentially an error-free mechanism that uses asupplied homologous DNA sequence as a template during DSB repair. Therate of homology directed repair (HDR) is a function of the distancebetween the mutation and the cut site so choosing overlapping or nearbytarget sites is important. Templates can include extra sequences flankedby the homologous regions or can contain a sequence that differs fromthe genomic sequence, thus allowing sequence editing.

The target gene can be associated with an immune response in a subject,wherein disrupting expression of the target gene will modulate theimmune response. For example, creating small insertions or deletions inthe target gene, and/or permanently deleting at least a portion of thetarget gene and/or inserting an exogenous sequence into the target genecan disrupt expression of target gene. The target gene sequence can beassociated with host versus graft response, a gene sequence associatedwith graft versus host response, a gene sequence encoding a checkpointinhibitor, and/or any combination thereof.

Target genes associated with a graft versus host (GVH) response include,for example, TRAC, CD3-epsilon (CDR), and combinations thereof.Permanently deleting at least a portion of these genes, creating smallinsertions or deletions in these genes, and/or inserting the nucleicacid encoding the CAR can reduce GVH response in a subject. Thereduction in GVH response can be partial or complete.

Target genes associated with a host versus graft (HVG) response include,for example, B2M, CIITA, RFX5, and combinations thereof. Permanentlydeleting at least a portion of these genes, creating small insertions ordeletions in these genes, and/or inserting the nucleic acid encoding theCAR can reduce HVG response in a subject. The reduction in HVG responsecan be partial or complete.

Target genes associated with immune suppression include, for example,checkpoint inhibitors such PD1, CTLA-4, and combinations thereof.Permanently deleting at least a portion of these genes, creating smallinsertions or deletions in these genes, and/or inserting the nucleicacid encoding the CAR can reduce immune suppression in a subject. Thereduction in immune suppression can be partial or complete.

The target gene can be associated with pharmacological modulation of acell, wherein disrupting expression of the target gene will modulate oneor pharmacological characteristics of the cell.

Target genes associated with pharmacological modulation of a cellinclude, for example, CD52. Permanently deleting at least a portion ofthese genes, creating small insertions or deletions in these genes,and/or inserting the nucleic acid encoding the CAR can positively ornegatively modulate one or pharmacological characteristics of the cell.The modulation of one or pharmacological characteristics of the cell canbe partial or complete. For example, permanently deleting at least aportion of these genes and inserting the nucleic acid encoding the CARcan positively impact or otherwise allow the CAR T cells to survive.Alternatively, permanently deleting at least a portion of these genesand inserting the nucleic acid encoding the CAR can negatively impact orotherwise kill the CAR T cells.

The donor templates used in the nucleic acid constructs encoding the CARcan also include a minigene or cDNA. For example, the minigene or cDNAcan comprise a gene sequence associated with pharmacological modulationof a cell. The gene sequence can encode Her2.

A Her2 gene sequence can be permanently inserted at a different locus inthe target gene or at a different locus in the genome from where thenucleic acid encoding the CAR construct is inserted.

Provided herein are methods to DSBs that induce small insertions ordeletions in a target gene resulting in the disruption (e.g.: reductionor elimination of gene expression and/or function) of the target gene.

Also, provided herein are methods to create DBSs and/or permanentlydelete within or near the target gene and to insert a nucleic acidconstruct encoding a CAR construct in the gene by inducing a doublestranded break with Cas9 and a sgRNA in a target sequence (or a pair ofdouble stranded breaks using two appropriate sgRNAs), and to provide adonor DNA template to induce Homology-Directed Repair (HDR). In someembodiments, the donor DNA template can be a short single strandedoligonucleotide, a short double stranded oligonucleotide, a long singleor double stranded DNA molecule. These methods use gRNAs and donor DNAmolecules for each target. In some embodiments, the donor DNA is singleor double stranded DNA having homologous arms to the correspondingregion. In some embodiments, the homologous arms are directed to thenuclease-targeted region of a gene selected from the group consisting ofTRAC (chr14:22278151-22553663), CD3ε (chr11:118301545-118319175), B2M(chr15:44708477-44721877), CIITA (chr16:10874198-10935281), RFX5(chr1:151337640-151350251), PD1 (chr2:241846881-241861908), CTLA-4(chr2:203864786-203876960), CD52 (chr1:26314957-26323523), PPP1R12C(chr19:55087913-55120559), and combinations thereof.

Provided herein are methods to knock-in target cDNA or a minigene(comprised of one or more exons and introns or natural or syntheticintrons) into the locus of the corresponding gene. These methods use apair of sgRNA targeting the first exon and/or the first intron of thetarget gene. In some embodiments, the donor DNA is single or doublestranded DNA having homologous arms to the nuclease-targeted region of aHer2 gene selected.

Provided herein are cellular methods (e.g., ex vivo or in vivo) methodsfor using genome engineering tools to create permanent changes to thegenome by: 1) creating DSBs to induce small insertions, deletions ormutations within or near a target gene, 2) deleting within or near thetarget gene or other DNA sequences that encode regulatory elements ofthe target gene and inserting, by HDR, a nucleic acid encoding aknock-in CAR construct within or near the target gene or other DNAsequences that encode regulatory elements of the target gene, or 3)creating DSBs within or near the target gene and inserting a nucleicacid construct within or near the target gene by HDR. Such methods useendonucleases, such as CRISPR-associated (Cas9, Cpf1 and the like)nucleases, to permanently delete, insert, edit, correct, or replace oneor more or exons or portions thereof (i.e., mutations within or nearcoding and/or splicing sequences) or insert in the genomic locus of thetarget gene or other DNA sequences that encode regulatory elements ofthe target gene. In this way, the examples set forth in the presentdisclosure restore the reading frame or the wild-type sequence of, orotherwise correct the gene with a single treatment (rather than deliverpotential therapies for the lifetime of the patient).

Provided herein are methods for treating a patient with a medicalcondition. An aspect of such method is an ex vivo cell-based therapy.For example, peripheral blood mononuclear cells are isolated from thepatient. Next, the chromosomal DNA of these cells is edited using thematerials and methods described herein. Finally, the genome-edited cellsare implanted into the patient.

Also provided herein are methods for reducing volume of a tumor in asubject, comprising administering to the subject a dose of apharmaceutical composition comprising a population of cells (e.g.,engineered T cells) of the present disclosure and reducing the volume ofthe tumor in the subject by at least 50% (e.g., at least 55%, at least60%, at least 65%, at least 70%, or at least 75%) relative to control(e.g., an untreated subject).

Further provided herein are methods for increasing survival rate in asubject, comprising administering to the subject a dose of apharmaceutical composition comprising a population of cells (e.g.,engineered T cells) of the present disclosure and increasing thesurvival rate in the subject by at least 50% % (e.g., at least 55%, atleast 60%, at least 65%, at least 70%, or at least 75%) relative tocontrol (e.g., an untreated subject).

In some embodiments, the composition comprises at 1×10⁵ to 1×10⁶ cells.In some embodiments, the pharmaceutical composition comprises at 1×10⁵to 2×10⁶ cells. For example, the composition may comprise 1×10⁵, 2×10⁵,3×10⁵, 4×10⁵, 5×10⁵, 6×10⁵, 7×10⁵, 8×10⁵, 9×10⁵, 1×10⁶, or 2×10⁶. Insome embodiments, the pharmaceutical composition comprises 1×10⁵ to5×10⁵ cells, 5×10⁵ to 1×10⁶ cells, or 5×10⁵ to 1.5×10⁶ cells.

Another aspect of an ex vivo cell-based therapy may include, forexample, isolating T cells from a donor. Next, the chromosomal DNA ofthese cells are edited using the materials and methods described herein.Finally, the genome-edited cells are implanted into a patient.

In certain aspects, T cells are isolated from more than one donor. Thesecells are edited using the materials and methods described herein.Finally, the genome-edited cells are implanted into a patient.

One advantage of an ex vivo cell therapy approach is the ability toconduct a comprehensive analysis of the therapeutic prior toadministration. Nuclease-based therapeutics have some level ofoff-target effects. Performing gene correction ex vivo allows one tofully characterize the corrected cell population prior to implantation.The present disclosure includes sequencing the entire genome of thecorrected cells to ensure that the off-target effects, if any, are ingenomic locations associated with minimal risk to the patient.Furthermore, populations of specific cells, including clonalpopulations, can be isolated prior to implantation.

Another embodiment of such methods also includes an in vivo basedtherapy. In this method, chromosomal DNA of the cells in the patient isedited using the materials and methods described herein. In someembodiments, the cells are T cells, such as CD4⁺ T-cells, CD8⁺ T-cells,or a combination thereof.

Also provided herein is a cellular method for editing the target gene ina cell by genome editing. For example, a cell is isolated from a patientor animal. Then, the chromosomal DNA of the cell is edited using thematerials and methods described herein.

The methods provided herein, in some embodiments, involve one or acombination of the following: 1) creating indels within or near thetarget gene or other DNA sequences that encode regulatory elements ofthe target gene, 2) deleting within or near the target gene or other DNAsequences that encode regulatory elements of the target gene, 3)inserting, by HDR or NHEJ, a nucleic acid encoding a knock-in CARconstruct within or near the target gene or other DNA sequences thatencode regulatory elements of the target gene, or 4) deletion of atleast a portion of the target gene and/or knocking-in target cDNA or aminigene (comprised of one or more exons or introns or natural orsynthetic introns) or introducing exogenous target DNA or cDNA sequenceor a fragment thereof into the locus of the gene.

The knock-in strategies utilize a donor DNA template inHomology-Directed Repair (HDR) or Non-Homologous End Joining (NHEJ). HDRin either strategy may be accomplished by making one or moresingle-stranded breaks (SSBs) or double-stranded breaks (DSBs) atspecific sites in the genome by using one or more endonucleases.

For example, the knock-in strategy involves knocking-in target cDNA or aminigene (comprised of, natural or synthetic enhancer and promoter, oneor more exons, and natural or synthetic introns, and natural orsynthetic 3′UTR and polyadenylation signal) into the locus of the geneusing a gRNA (e.g., crRNA+tracrRNA, or sgRNA) or a pair of sgRNAstargeting upstream of or in the first or other exon and/or intron of thetarget gene. The donor DNA can be a single or double stranded DNA havinghomologous arms to the nuclease-targeted region of the target gene. Forexample, the donor DNA can be a single or double stranded DNA havinghomologous arms to the nuclease-targeted region of a gene selected fromthe group consisting of TRAC (chr14:22278151-22553663), CD3ε(chr11:118301545-118319175), B2M (chr15:44708477-44721877), CIITA(chr16:10874198-10935281), RFX5 (chr1:151337640-151350251), PD1(chr2:241846881-241861908), CTLA-4 (chr2:203864786-203876960), CD52(chr1:26314957-26323523), PPP1R12C (chr19:55087913-55120559), andcombinations thereof.

For example, the deletion strategy involves, in some aspects, deletingone or more introns, exons, regulatory regions, of the target gene,partial segments of the target gene or the entire target gene sequenceusing one or more endonucleases and one or more gRNAs or sgRNAs.

As another example, the deletion strategy involves, in some aspects,deleting one or more nucleic acids, of one or more target genes,resulting in small insertions or deletions (indels) using one or moreendonucleases and one or more gRNAs or sgRNAs.

In addition to the above genome editing strategies, another exampleediting strategy involves modulating expression, function, or activityof a target gene by editing in the regulatory sequence.

In addition to the editing options listed above, Cas9 or similarproteins can be used to target effector domains to the same target sitesthat may be identified for editing, or additional target sites withinrange of the effector domain. A range of chromatin modifying enzymes,methylases or demethlyases may be used to alter expression of the targetgene. One possibility is increasing the expression of the target proteinif the mutation leads to lower activity. These types of epigeneticregulation have some advantages, particularly as they are limited inpossible off-target effects.

A number of types of genomic target sites are present in addition tomutations in the coding and splicing sequences.

The regulation of transcription and translation implicates a number ofdifferent classes of sites that interact with cellular proteins ornucleotides. Often the DNA binding sites of transcription factors orother proteins can be targeted for mutation or deletion to study therole of the site, though they can also be targeted to change geneexpression. Sites can be added through non-homologous end joining NHEJor direct genome editing by homology directed repair (HDR). Increaseduse of genome sequencing, RNA expression and genome-wide studies oftranscription factor binding have increased the ability to identify howthe sites lead to developmental or temporal gene regulation. Thesecontrol systems may be direct or may involve extensive cooperativeregulation that can require the integration of activities from multipleenhancers. Transcription factors typically bind 6-12 bp-long degenerateDNA sequences. The low level of specificity provided by individual sitessuggests that complex interactions and rules are involved in binding andthe functional outcome. Binding sites with less degeneracy may providesimpler means of regulation. Artificial transcription factors can bedesigned to specify longer sequences that have less similar sequences inthe genome and have lower potential for off-target cleavage. Any ofthese types of binding sites can be mutated, deleted or even created toenable changes in gene regulation or expression (Canver, M. C. et al.,Nature (2015)).

Another class of gene regulatory regions having these features ismicroRNA (miRNA) binding sites. miRNAs are non-coding RNAs that play keyroles in posttranscriptional gene regulation. miRNA may regulate theexpression of 30% of all mammalian protein-encoding genes. Specific andpotent gene silencing by double stranded RNA (RNAi) was discovered, plusadditional small noncoding RNA (Canver, M. C. et al., Nature (2015)).The largest class of noncoding RNAs important for gene silencing aremiRNAs. In mammals, miRNAs are first transcribed as long RNAtranscripts, which can be separate transcriptional units, part ofprotein introns, or other transcripts. The long transcripts are calledprimary miRNA (pri-miRNA) that include imperfectly base-paired hairpinstructures. These pri-miRNA are cleaved into one or more shorterprecursor miRNAs (pre-miRNAs) by Microprocessor, a protein complex inthe nucleus, involving Drosha.

Pre-miRNAs are short stem loops ˜70 nucleotides in length with a2-nucleotide 3′-overhang that are exported, into the mature 19-25nucleotide miRNA:miRNA* duplexes. The miRNA strand with lower basepairing stability (the guide strand) can be loaded onto the RNA-inducedsilencing complex (RISC). The passenger guide strand (marked with *),may be functional, but is usually degraded. The mature miRNA tethersRISC to partly complementary sequence motifs in target mRNAspredominantly found within the 3′ untranslated regions (UTRs) andinduces posttranscriptional gene silencing (Bartel, D. P. Cell 136,215-233 (2009); Saj, A. & Lai, E. C. Curr Opin Genet Dev 21, 504-510(2011)).

miRNAs are important in development, differentiation, cell cycle andgrowth control, and in virtually all biological pathways in mammals andother multicellular organisms. miRNAs are also involved in cell cyclecontrol, apoptosis and stem cell differentiation, hematopoiesis,hypoxia, muscle development, neurogenesis, insulin secretion,cholesterol metabolism, aging, viral replication and immune responses.

A single miRNA can target hundreds of different mRNA transcripts, whilean individual transcript can be targeted by many different miRNAs. Morethan 28645 microRNAs have been annotated in the latest release ofmiRBase (v.21). Some miRNAs are encoded by multiple loci, some of whichare expressed from tandemly co-transcribed clusters. The features allowfor complex regulatory networks with multiple pathways and feedbackcontrols. miRNAs are integral parts of these feedback and regulatorycircuits and can help regulate gene expression by keeping proteinproduction within limits (Herranz, H. & Cohen, S. M. Genes Dev 24,1339-1344 (2010); Posadas, D. M. & Carthew, R. W. Curr Opin Genet Dev27, 1-6 (2014)).

miRNAs are also important in a large number of human diseases that areassociated with abnormal miRNA expression. This association underscoresthe importance of the miRNA regulatory pathway. Recent miRNA deletionstudies have linked miRNA with regulation of the immune responses(Stern-Ginossar, N. et al., Science 317, 376-381 (2007)).

miRNAs also have a strong link to cancer and may play a role indifferent types of cancer. miRNAs have been found to be downregulated ina number of tumors. miRNAs are important in the regulation of keycancer-related pathways, such as cell cycle control and the DNA damageresponse, and are therefore used in diagnosis and are being targetedclinically. MicroRNAs delicately regulate the balance of angiogenesis,such that experiments depleting all microRNAs suppresses tumorangiogenesis (Chen, S. et al., Genes Dev 28, 1054-1067 (2014)).

As has been shown for protein coding genes, miRNA genes are also subjectto epigenetic changes occurring with cancer. Many miRNA loci areassociated with CpG islands increasing their opportunity for regulationby DNA methylation (Weber, B., Stresemann, C., Brueckner, B. & Lyko, F.Cell Cycle 6, 1001-1005 (2007)). The majority of studies have usedtreatment with chromatin remodeling drugs to reveal epigeneticallysilenced miRNAs.

In addition to their role in RNA silencing, miRNA can also activatetranslation (Posadas, D. M. & Carthew, R. W. Curr Opin Genet Dev 27, 1-6(2014)). Knocking out these sites may lead to decreased expression ofthe targeted gene, while introducing these sites may increaseexpression.

Individual miRNAs can be knocked out most effectively by mutating theseed sequence (bases 2-8 of the microRNA), which is important forbinding specificity. Cleavage in this region, followed by mis-repair byNHEJ can effectively abolish miRNA function by blocking binding totarget sites. miRNA could also be inhibited by specific targeting of thespecial loop region adjacent to the palindromic sequence. Catalyticallyinactive Cas9 can also be used to inhibit shRNA expression (Zhao, Y. etal., Sci Rep 4, 3943 (2014)). In addition to targeting the miRNA, thebinding sites can also be targeted and mutated to prevent the silencingby miRNA.

Chimeric Antigen Receptor (CAR) T Cells

A chimeric antigen receptor refers to an artificial immune cell receptorthat is engineered to recognize and bind to an antigen expressed bytumor cells. Generally, a CAR is designed for a T cell and is a chimeraof a signaling domain of the T-cell receptor (TcR) complex and anantigen-recognizing domain (e.g., a single chain fragment (scFv) of anantibody or other antibody fragment) (Enblad et al., Human Gene Therapy.2015; 26(8):498-505). A T cell that expresses a CAR is referred to as aCAR T cell. CARs have the ability to redirect T-cell specificity andreactivity toward a selected target in a non-MHC-restricted manner. Thenon-MHC-restricted antigen recognition gives T-cells expressing CARs theability to recognize an antigen independent of antigen processing, thusbypassing a major mechanism of tumor escape. Moreover, when expressed inT-cells, CARs advantageously do not dimerize with endogenous T-cellreceptor (TCR) alpha and beta chains.

There are four generations of CARs, each of which contains differentcomponents. First generation CARs join an antibody-derived scFv to theCD3zeta (ζ or z) intracellular signaling domain of the T-cell receptorthrough hinge and transmembrane domains. Second generation CARsincorporate an additional domain, e.g., CD28, 4-1BB (41BB), or ICOS, tosupply a costimulatory signal. Third-generation CARs contain twocostimulatory domains fused with the TcR CD3-ζ chain. Third-generationcostimulatory domains may include, e.g., a combination of CD3z, CD27,CD28, 4-1BB, ICOS, or OX40. CARs, in some embodiments, contain anectodomain (e.g., CD3ζ), commonly derived from a single chain variablefragment (scFv), a hinge, a transmembrane domain, and an endodomain withone (first generation), two (second generation), or three (thirdgeneration) signaling domains derived from CD3Z and/or co-stimulatorymolecules (Maude et al., Blood. 2015; 125(26):4017-4023; Kakarla andGottschalk, Cancer J. 2014; 20(2):151-155).

CARs typically differ in their functional properties. The CD3 signalingdomain of the T-cell receptor, when engaged, will activate and induceproliferation of T-cells but can lead to anergy (a lack of reaction bythe body's defense mechanisms, resulting in direct induction ofperipheral lymphocyte tolerance). Lymphocytes are considered anergicwhen they fail to respond to a specific antigen. The addition of acostimulatory domain in second-generation CARs improved replicativecapacity and persistence of modified T-cells. Similar antitumor effectsare observed in vitro with CD28 or 4-1BB CARs, but preclinical in vivostudies suggest that 4-1BB CARs may produce superior proliferationand/or persistence. Clinical trials suggest that both of thesesecond-generation CARs are capable of inducing substantial T-cellproliferation in vivo, but CARs containing the 4-1BB costimulatorydomain appear to persist longer. Third generation CARs combine multiplesignaling domains (costimulatory) to augment potency.

In some embodiments, a chimeric antigen receptor is a first generationCAR. In other embodiments, a chimeric antigen receptor is a secondgeneration CAR. In yet other embodiments, a chimeric antigen receptor isa third generation CAR.

A CAR, in some embodiments, comprises an extracellular (ecto) domaincomprising an antigen binding domain (e.g., an antibody, such as anscFv), a transmembrane domain, and a cytoplasmic (endo) domain.

Ectodomain. The ectodomain is the region of the CAR that is exposed tothe extracellular fluid and, in some embodiments, includes an antigenbinding domain, and optionally a signal peptide, a spacer domain, and/ora hinge domain. In some embodiments, the antigen binding domain is asingle-chain variable fragment (scFv) that include the light and heavychains of immunoglobins connected with a short linker peptide (e.g., anyone of SEQ ID NO: 1591, 1594, or 1597). The linker, in some embodiments,includes hydrophilic residues with stretches of glycine and serine forflexibility as well as stretches of glutamate and lysine for addedsolubility. A single-chain variable fragment (scFv) is not actually afragment of an antibody, but instead is a fusion protein of the variableregions of the heavy (VH) and light chains (VL) of immunoglobulins,connected with a short linker peptide of ten to about 25 amino acids.The linker is usually rich in glycine for flexibility, as well as serineor threonine for solubility, and can either connect the N-terminus ofthe VH with the C-terminus of the VL, or vice versa. This proteinretains the specificity of the original immunoglobulin, despite removalof the constant regions and the introduction of the linker. In someembodiments, the scFv of the present disclosure is humanized. In otherembodiments, the scFv is fully human. In yet other embodiments, the scFvis a chimera (e.g., of mouse and human sequence). In some embodiments,the scFv is an anti-CD70 scFv (binds specifically to CD70). Non-limitingexamples of anti-CD70 scFv proteins and heavy and/or light chains thatmay be used as provided herein include those that comprise any one ofSEQ ID NOs: 1499 (scFv), 1500 (scFV), 1592 (heavy chain), or 1593 (lightchain).

The signal peptide can enhance the antigen specificity of CAR binding.Signal peptides can be derived from antibodies, such as, but not limitedto, CD8, as well as epitope tags such as, but not limited to, GST orFLAG. Examples of signal peptides include MLLLVTSLLLCELPHPAFLLIP (SEQ IDNO: 1598) and MALPVTALLLPLALLLHAARP (SEQ ID NO: 1586). Other signalpeptides may be used.

In some embodiments, a spacer domain or hinge domain is located betweenan extracellular domain (comprising the antigen binding domain) and atransmembrane domain of a CAR, or between a cytoplasmic domain and atransmembrane domain of the CAR. A spacer domain is any oligopeptide orpolypeptide that functions to link the transmembrane domain to theextracellular domain and/or the cytoplasmic domain in the polypeptidechain. A hinge domain is any oligopeptide or polypeptide that functionsto provide flexibility to the CAR, or domains thereof, or to preventsteric hindrance of the CAR, or domains thereof. In some embodiments, aspacer domain or a hinge domain may comprise up to 300 amino acids(e.g., 10 to 100 amino acids, or 5 to 20 amino acids). In someembodiments, one or more spacer domain(s) may be included in otherregions of a CAR. In some embodiments, the hinge domain is a CD8 hingedomain. Other hinge domains may be used.

Transmembrane Domain. The transmembrane domain is a hydrophobic alphahelix that spans the membrane. The transmembrane domain providesstability of the CAR. In some embodiments, the transmembrane domain of aCAR as provided herein is a CD8 transmembrane domain. In otherembodiments, the transmembrane domain is a CD28 transmembrane domain. Inyet other embodiments, the transmembrane domain is a chimera of a CD8and CD28 transmembrane domain. Other transmembrane domains may be usedas provided herein. In some embodiments, the transmembrane domain is aCD8a transmembrane domain, optionally including a 5′ linker.

Endodomain. The endodomain is the functional end of the receptor.Following antigen recognition, receptors cluster and a signal istransmitted to the cell. The most commonly used endodomain component isCD3-zeta, which contains three (3) ITAMs. This transmits an activationsignal to the T cell after the antigen is bound. In many cases, CD3-zetamay not provide a fully competent activation signal and, thus, aco-stimulatory signaling is used. For example, CD28 and/or 4-1BB may beused with CD3-zeta (CD3) to transmit a proliferative/survival signal.Thus, in some embodiments, the co-stimulatory molecule of a CAR asprovided herein is a CD28 co-stimulatory molecule. In other embodiments,the co-stimulatory molecule is a 4-1BB co-stimulatory molecule. In someembodiments, a CAR includes CD3 and CD28. In other embodiments, a CARincludes CD3-zeta and 4-1BB. In still other embodiments, a CAR includesCD3ζ, CD28, and 4-1BB. Non-limiting examples of co-stimulatory moleculesthat may be used herein include those encoded by the nucleotide sequenceof SEQ ID NO: 1377 (CD3-zeta), SEQ ID NO 1336 (CD28), and/or SEQ ID NO:1339 (4-1BB).

Human Cells

As described and illustrated herein, the principal targets for geneediting are human cells. For example, primary human T cells, CD4+ and/orCD8+, can be edited. They can be isolated from peripheral bloodmononuclear cell isolations.

Gene editing can be verified by alterations in target surface proteinexpression as well as analysis of DNA by PCR and/or sequencing.

Edited cells can have a selective advantage. MHC-I and/or MHC-II as wellas PDCD1 or CTLA4 knockout T cells can persist longer in patients.

Edited cells can be assayed for off-target gene editing as well astranslocations. They can also be tested for the ability to grow incytokine free media. If edited cells display low off-target activity andminimal translocations, as well as have the inability to grow incytokine free media, they will be deemed safe.

Primary human T cells can be isolated from peripheral blood mononuclearcells (PBMC) isolated from leukopaks. T cells can be expanded from PBMCby treatment with anti-CD3/CD28 antibody-coupled nanoparticles or beads.Activated T cells can be electroporated with RNP(s) containing Cas9complexed to sgRNA. Cells can then be treated with AAV6 virus containingdonor template DNA when HDR is needed, for example, for insertion of anucleic acid encoding a CAR construct. Cells can then be expanded for1-2 weeks in liquid culture. When TCR negative cells are required,edited cells can be selected for by antibody/column based methods, suchas, for example, MACS.

By performing gene editing in allogeneic cells that are derived from adonor who does not have or is not suspected of having a medicalcondition to be treated, it is possible to generate cells that can besafely re-introduced into the patient, and effectively give rise to apopulation of cells that are effective in ameliorating one or moreclinical conditions associated with the patient's disease.

By performing gene editing in autologous cells that are derived from andtherefore already completely immunologically matched with the patient inneed, it is possible to generate cells that can be safely re-introducedinto the patient, and effectively give rise to a population of cellsthat are effective in ameliorating one or more clinical conditionsassociated with the patient's disease.

Progenitor cells (also referred to as stem cells herein) are capable ofboth proliferation and giving rise to more progenitor cells, these inturn having the ability to generate a large number of mother cells thatcan in turn give rise to differentiated or differentiable daughtercells. The daughter cells themselves can be induced to proliferate andproduce progeny that subsequently differentiate into one or more maturecell types, while also retaining one or more cells with parentaldevelopmental potential. The term “stem cell” refers then, to a cellwith the capacity or potential, under particular circumstances, todifferentiate to a more specialized or differentiated phenotype, andwhich retains the capacity, under certain circumstances, to proliferatewithout substantially differentiating. In one aspect, the termprogenitor or stem cell refers to a generalized mother cell whosedescendants (progeny) specialize, often in different directions, bydifferentiation, e.g., by acquiring completely individual characters, asoccurs in progressive diversification of embryonic cells and tissues.Cellular differentiation is a complex process typically occurringthrough many cell divisions. A differentiated cell may derive from amultipotent cell that itself is derived from a multipotent cell, and soon. While each of these multipotent cells may be considered stem cells,the range of cell types that each can give rise to may varyconsiderably. Some differentiated cells also have the capacity to giverise to cells of greater developmental potential. Such capacity may benatural or may be induced artificially upon treatment with variousfactors. In many biological instances, stem cells are also “multipotent”because they can produce progeny of more than one distinct cell type,but this is not required for “stem-ness.”

Self-renewal is another important aspect of the stem cell. In theory,self-renewal can occur by either of two major mechanisms. Stem cells maydivide asymmetrically, with one daughter retaining the stem state andthe other daughter expressing some distinct other specific function andphenotype. Alternatively, some of the stem cells in a population candivide symmetrically into two stems, thus maintaining some stem cells inthe population as a whole, while other cells in the population give riseto differentiated progeny only. Generally, “progenitor cells” have acellular phenotype that is more primitive (i.e., is at an earlier stepalong a developmental pathway or progression than is a fullydifferentiated cell). Often, progenitor cells also have significant orvery high proliferative potential. Progenitor cells can give rise tomultiple distinct differentiated cell types or to a singledifferentiated cell type, depending on the developmental pathway and onthe environment in which the cells develop and differentiate.

In the context of cell ontogeny, the adjective “differentiated,” or“differentiating” is a relative term. A “differentiated cell” is a cellthat has progressed further down the developmental pathway than the cellto which it is being compared. Thus, stem cells can differentiate intolineage-restricted precursor cells (such as a myocyte progenitor cell),which in turn can differentiate into other types of precursor cellsfurther down the pathway (such as a myocyte precursor), and then to anend-stage differentiated cell, such as a myocyte, which plays acharacteristic role in a certain tissue type, and may or may not retainthe capacity to proliferate further.

The term “hematopoietic progenitor cell” refers to cells of a stem celllineage that give rise to all the blood cell types, including erythroid(erythrocytes or red blood cells (RBCs)), myeloid (monocytes andmacrophages, neutrophils, basophils, eosinophils,megakaryocytes/platelets, and dendritic cells), and lymphoid (T-cells,B-cells, NK-cells).

Isolating a Peripheral Blood Mononuclear Cell

Peripheral blood mononuclear cells may be isolated according to anymethod known in the art. For example, white blood cells may be isolatedfrom a liquid sample by centrifugation and cell culturing.

Treating a Patient with GCSF

A patient may optionally be treated with granulocyte colony stimulatingfactor (GCSF) in accordance with any method known in the art. In someembodiments, the GCSF is administered in combination with Plerixaflor.

Animal Models

For efficacy studies, NOG or NSG mice can be used. They can betransplanted with human lymphoma cell lines and subsequentlytransplanted with edited human CAR−T cells. Loss/prevention of lymphomacells can indicate the efficacy of edited T cells.

The safety of TCR edited T cells can be assessed in NOG or NSG mice.Human T cells transplanted into these mice can cause a lethal xenogeneicgraft versus host disease (GVHD). Removal of the TCR by gene editingshould alleviate this type of GVHD.

Genome Editing

Genome editing generally refers to the process of modifying thenucleotide sequence of a genome, preferably in a precise orpre-determined manner Examples of methods of genome editing describedherein include methods of using site-directed nucleases to cutdeoxyribonucleic acid (DNA) at precise target locations in the genome,thereby creating single-strand or double-strand DNA breaks at particularlocations within the genome. Such breaks may be and regularly arerepaired by natural, endogenous cellular processes, such ashomology-directed repair (HDR) and non-homologous end-joining (NHEJ), asrecently reviewed in Cox et al., Nature Medicine 21(2), 121-31 (2015).These two main DNA repair processes consist of a family of alternativepathways. NHEJ directly joins the DNA ends resulting from adouble-strand break, sometimes with the loss or addition of nucleotidesequence, which may disrupt or enhance gene expression. HDR utilizes ahomologous sequence, or donor sequence, as a template for inserting adefined DNA sequence at the break point. The homologous sequence may bein the endogenous genome, such as a sister chromatid. Alternatively, thedonor may be an exogenous nucleic acid, such as a plasmid, asingle-strand oligonucleotide, a double-stranded oligonucleotide, aduplex oligonucleotide or a virus, that has regions of high homologywith the nuclease-cleaved locus, but which may also contain additionalsequence or sequence changes including deletions that may beincorporated into the cleaved target locus. A third repair mechanism ismicrohomology-mediated end joining (MMEJ), also referred to as“Alternative NHEJ”, in which the genetic outcome is similar to NHEJ inthat small deletions and insertions can occur at the cleavage site. MMEJmakes use of homologous sequences of a few basepairs flanking the DNAbreak site to drive a more favored DNA end joining repair outcome, andrecent reports have further elucidated the molecular mechanism of thisprocess; see, e.g., Cho and Greenberg, Nature 518, 174-76 (2015); Kentet al., Nature Structural and Molecular Biology, Adv. Onlinedoi:10.1038/nsmb.2961(2015); Mateos-Gomez et al., Nature 518, 254-57(2015); Ceccaldi et al., Nature 528, 258-62 (2015). In some instances,it may be possible to predict likely repair outcomes based on analysisof potential microhomologies at the site of the DNA break.

Each of these genome editing mechanisms can be used to create desiredgenomic alterations. A step in the genome editing process is to createone or two DNA breaks, the latter as double-strand breaks or as twosingle-stranded breaks, in the target locus as close as possible to thesite of intended mutation. This can be achieved via the use ofsite-directed polypeptides, as described and illustrated herein.

Site-directed polypeptides, such as a DNA endonuclease, can introducedouble-strand breaks or single-strand breaks in nucleic acids, e.g.,genomic DNA. The double-strand break can stimulate a cell's endogenousDNA-repair pathways (e.g., homology-dependent repair or non-homologousend joining or alternative non-homologous end joining (A-NHEJ) ormicrohomology-mediated end joining). NHEJ can repair cleaved targetnucleic acid without the need for a homologous template. This cansometimes result in small deletions or insertions (indels) in the targetnucleic acid at the site of cleavage, and can lead to disruption oralteration of gene expression. HDR can occur when a homologous repairtemplate, or donor, is available. The homologous donor templatecomprises sequences that are homologous to sequences flanking the targetnucleic acid cleavage site. The sister chromatid is generally used bythe cell as the repair template. However, for the purposes of genomeediting, the repair template is often supplied as an exogenous nucleicacid, such as a plasmid, duplex oligonucleotide, single-strandoligonucleotide, double-stranded oligonucleotide, or viral nucleic acid.With exogenous donor templates, it is common to introduce an additionalnucleic acid sequence (such as a transgene) or modification (such as asingle or multiple base change or a deletion) between the flankingregions of homology so that the additional or altered nucleic acidsequence also becomes incorporated into the target locus. MMEJ resultsin a genetic outcome that is similar to NHEJ in that small deletions andinsertions can occur at the cleavage site. MMEJ makes use of homologoussequences of a few basepairs flanking the cleavage site to drive afavored end-joining DNA repair outcome. In some instances, it may bepossible to predict likely repair outcomes based on analysis ofpotential microhomologies in the nuclease target regions.

Thus, in some embodiments, either non-homologous end joining orhomologous recombination is used to insert an exogenous polynucleotidesequence into the target nucleic acid cleavage site. An exogenouspolynucleotide sequence is termed a donor polynucleotide (or donor ordonor sequence or polynucleotide donor template) herein. In someembodiments, the donor polynucleotide, a portion of the donorpolynucleotide, a copy of the donor polynucleotide, or a portion of acopy of the donor polynucleotide is inserted into the target nucleicacid cleavage site. In some embodiments, the donor polynucleotide is anexogenous polynucleotide sequence, i.e., a sequence that does notnaturally occur at the target nucleic acid cleavage site.

The modifications of the target DNA due to NHEJ and/or HDR can lead to,for example, mutations, deletions, alterations, integrations, genecorrection, gene replacement, gene tagging, transgene insertion,nucleotide deletion, gene disruption, translocations and/or genemutation. The processes of deleting genomic DNA and integratingnon-native nucleic acid into genomic DNA are examples of genome editing.

CRISPR Endonuclease System

A CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)genomic locus can be found in the genomes of many prokaryotes (e.g.,bacteria and archaea). In prokaryotes, the CRISPR locus encodes productsthat function as a type of immune system to help defend the prokaryotesagainst foreign invaders, such as virus and phage. There are threestages of CRISPR locus function: integration of new sequences into theCRISPR locus, expression of CRISPR RNA (crRNA), and silencing of foreigninvader nucleic acid. Five types of CRISPR systems (e.g., Type I, TypeII, Type III, Type U, and Type V) have been identified.

A CRISPR locus includes a number of short repeating sequences referredto as “repeats.” When expressed, the repeats can form secondarystructures (e.g., hairpins) and/or comprise unstructured single-strandedsequences. The repeats usually occur in clusters and frequently divergebetween species. The repeats are regularly interspaced with uniqueintervening sequences referred to as “spacers,” resulting in arepeat-spacer-repeat locus architecture. The spacers are identical to orhave high homology with known foreign invader sequences. A spacer-repeatunit encodes a crisprRNA (crRNA), which is processed into a mature formof the spacer-repeat unit. A crRNA comprises a “seed” or spacer sequencethat is involved in targeting a target nucleic acid (in the naturallyoccurring form in prokaryotes, the spacer sequence targets the foreigninvader nucleic acid). A spacer sequence is located at the 5′ or 3′ endof the crRNA.

A CRISPR locus also comprises polynucleotide sequences encoding CRISPRAssociated (Cas) genes. Cas genes encode endonucleases involved in thebiogenesis and the interference stages of crRNA function in prokaryotes.Some Cas genes comprise homologous secondary and/or tertiary structures.

Type II CRISPR Systems

crRNA biogenesis in a Type II CRISPR system in nature requires atrans-activating CRISPR RNA (tracrRNA). The tracrRNA is modified byendogenous RNaseIII, and then hybridizes to a crRNA repeat in thepre-crRNA array. Endogenous RNaseIII is recruited to cleave thepre-crRNA. Cleaved crRNAs is subjected to exoribonuclease trimming toproduce the mature crRNA form (e.g., 5′ trimming) The tracrRNA remainshybridized to the crRNA, and the tracrRNA and the crRNA associate with asite-directed polypeptide (e.g., Cas9). The crRNA of thecrRNA-tracrRNA-Cas9 complex guides the complex to a target nucleic acidto which the crRNA can hybridize. Hybridization of the crRNA to thetarget nucleic acid activates Cas9 for targeted nucleic acid cleavage.The target nucleic acid in a Type II CRISPR system is referred to as aprotospacer adjacent motif (PAM). In nature, the PAM is essential tofacilitate binding of a site-directed polypeptide (e.g., Cas9) to thetarget nucleic acid. Type II systems (also referred to as Nmeni orCASS4) are further subdivided into Type II-A (CASS4) and II-B (CASS4a).Jinek et al., Science, 337(6096):816-821 (2012) showed that theCRISPR/Cas9 system is useful for RNA-programmable genome editing, andinternational patent application publication number WO2013/176772provides numerous examples and applications of the CRISPR/Casendonuclease system for site-specific gene editing.

Type V CRISPR Systems

Type V CRISPR systems have several important differences from Type IIsystems. For example, Cpf1 is a single RNA-guided endonuclease that, incontrast to Type II systems, lacks tracrRNA. In fact, Cpf1-associatedCRISPR arrays are processed into mature crRNAs without the requirementof an additional trans-activating tracrRNA. The Type V CRISPR array isprocessed into short mature crRNAs of 42-44 nucleotides in length, witheach mature crRNA beginning with 19 nucleotides of direct repeatfollowed by 23-25 nucleotides of spacer sequence. In contrast, maturecrRNAs in Type II systems start with 20-24 nucleotides of spacersequence followed by about 22 nucleotides of direct repeat. Also, Cpf1utilizes a T-rich protospacer-adjacent motif such that Cpf1-crRNAcomplexes efficiently cleave target DNA preceded by a short T-rich PAM,which is in contrast to the G-rich PAM following the target DNA for TypeII systems. Thus, Type V systems cleave at a point that is distant fromthe PAM, while Type II systems cleave at a point that is adjacent to thePAM. In addition, in contrast to Type II systems, Cpf1 cleaves DNA via astaggered DNA double-stranded break with a 4 or 5 nucleotide 5′overhang. Type II systems cleave via a blunt double-stranded break.Similar to Type II systems, Cpf1 contains a predicted RuvC-likeendonuclease domain, but lacks a second HNH endonuclease domain, whichis in contrast to Type II systems.

Cas Genes/Polypeptides and Protospacer Adjacent Motifs

Exemplary CRISPR/Cas polypeptides include the Cas9 polypeptides in Fig 1of Fonfara et al., Nucleic Acids Research, 42: 2577-2590 (2014). TheCRISPR/Cas gene naming system has undergone extensive rewriting sincethe Cas genes were discovered. Fig. 5 of Fonfara, supra, provides PAMsequences for the Cas9 polypeptides from various species.

Site-Directed Polypeptides

A site-directed polypeptide is a nuclease used in genome editing tocleave DNA. The site-directed may be administered to a cell or a patientas either: one or more polypeptides, or one or more mRNAs encoding thepolypeptide.

In the context of a CRISPR/Cas or CRISPR/Cpf1 system, the site-directedpolypeptide can bind to a guide RNA that, in turn, specifies the site inthe target DNA to which the polypeptide is directed. In embodiments ofthe CRISPR/Cas or CRISPR/Cpf1 systems herein, the site-directedpolypeptide is an endonuclease, such as a DNA endonuclease.

In some embodiments, a site-directed polypeptide comprises a pluralityof nucleic acid-cleaving (i.e., nuclease) domains. Two or more nucleicacid-cleaving domains can be linked together via a linker. For example,the linker comprises a flexible linker. In some embodiments, linkerscomprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 30, 35, 40 or more amino acids in length.

Naturally-occurring wild-type Cas9 enzymes comprise two nucleasedomains, a HNH nuclease domain and a RuvC domain. Herein, the “Cas9”refers to both naturally-occurring and recombinant Cas9s. Cas9 enzymescontemplated herein comprises a HNH or HNH-like nuclease domain, and/ora RuvC or RuvC-like nuclease domain.

HNH or HNH-like domains comprise a McrA-like fold. HNH or HNH-likedomains comprises two antiparallel β-strands and an α-helix. HNH orHNH-like domains comprises a metal binding site (e.g., a divalent cationbinding site). HNH or HNH-like domains can cleave one strand of a targetnucleic acid (e.g., the complementary strand of the crRNA targetedstrand).

RuvC or RuvC-like domains comprise an RNaseH or RNaseH-like fold.RuvC/RNaseH domains are involved in a diverse set of nucleic acid-basedfunctions including acting on both RNA and DNA. The RNaseH domaincomprises 5 β-strands surrounded by a plurality of α-helices.RuvC/RNaseH or RuvC/RNaseH-like domains comprise a metal binding site(e.g., a divalent cation binding site). RuvC/RNaseH or RuvC/RNaseH-likedomains can cleave one strand of a target nucleic acid (e.g., thenon-complementary strand of a double-stranded target DNA).

Site-directed polypeptides can introduce double-strand breaks orsingle-strand breaks in nucleic acids, e.g., genomic DNA. Thedouble-strand break can stimulate a cell's endogenous DNA-repairpathways (e.g., homology-dependent repair (HDR) or non-homologousend-joining (NHEJ) or alternative non-homologous end joining (A-NHEJ) ormicrohomology-mediated end joining (MMEJ)). NHEJ can repair cleavedtarget nucleic acid without the need for a homologous template. This cansometimes result in small deletions or insertions (indels) in the targetnucleic acid at the site of cleavage, and can lead to disruption oralteration of gene expression. HDR can occur when a homologous repairtemplate, or donor, is available. The homologous donor templatecomprises sequences that are homologous to sequences flanking the targetnucleic acid cleavage site. The sister chromatid is generally used bythe cell as the repair template. However, for the purposes of genomeediting, the repair template is often supplied as an exogenous nucleicacid, such as a plasmid, duplex oligonucleotide, single-strandoligonucleotide or viral nucleic acid. With exogenous donor templates,it is common to introduce an additional nucleic acid sequence (such as atransgene) or modification (such as a single or multiple base change ora deletion) between the flanking regions of homology so that theadditional or altered nucleic acid sequence also becomes incorporatedinto the target locus. MMEJ results in a genetic outcome that is similarto NHEJ in that small deletions and insertions can occur at the cleavagesite. MMEJ makes use of homologous sequences of a few basepairs flankingthe cleavage site to drive a favored end-joining DNA repair outcome. Insome instances, it may be possible to predict likely repair outcomesbased on analysis of potential microhomologies in the nuclease targetregions.

Thus, in some embodiments, homologous recombination is used to insert anexogenous polynucleotide sequence into the target nucleic acid cleavagesite. An exogenous polynucleotide sequence is termed a donorpolynucleotide (or donor or donor sequence) herein. In some embodiments,the donor polynucleotide, a portion of the donor polynucleotide, a copyof the donor polynucleotide, or a portion of a copy of the donorpolynucleotide is inserted into the target nucleic acid cleavage site.In some embodiments, the donor polynucleotide is an exogenouspolynucleotide sequence, i.e., a sequence that does not naturally occurat the target nucleic acid cleavage site.

The modifications of the target DNA due to NHEJ and/or HDR can lead to,for example, mutations, deletions, alterations, integrations, genecorrection, gene replacement, gene tagging, transgene insertion,nucleotide deletion, gene disruption, translocations and/or genemutation. The processes of deleting genomic DNA and integratingnon-native nucleic acid into genomic DNA are examples of genome editing.

In some embodiments, the site-directed polypeptide comprises an aminoacid sequence having at least 10%, at least 15%, at least 20%, at least30%, at least 40%, at least 50%, at least 60%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, at least99%, or 100% amino acid sequence identity to a wild-type exemplarysite-directed polypeptide [e.g., Cas9 from S. pyogenes, US2014/0068797Sequence ID No. 8 or Sapranauskas et al., Nucleic Acids Res, 39(21):9275-9282 (2011)], and various other site-directed polypeptides. In someembodiments, the site-directed polypeptide comprises at least 70, 75,80, 85, 90, 95, 97, 99, or 100% identity to a wild-type site-directedpolypeptide (e.g., Cas9 from S. pyogenes, supra) over 10 contiguousamino acids.

In some embodiments, the site-directed polypeptide comprises an aminoacid sequence having at least 10%, at least 15%, at least 20%, at least30%, at least 40%, at least 50%, at least 60%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, at least99%, or 100% amino acid sequence identity to the nuclease domain of awild-type exemplary site-directed polypeptide (e.g., Cas9 from S.pyogenes, supra).

In some embodiments, the site-directed polypeptide comprises at most:70, 75, 80, 85, 90, 95, 97, 99, or 100% identity to a wild-typesite-directed polypeptide (e.g., Cas9 from S. pyogenes, supra) over 10contiguous amino acids. In some embodiments, the site-directedpolypeptide comprises at least: 70, 75, 80, 85, 90, 95, 97, 99, or 100%identity to a wild-type site-directed polypeptide (e.g., Cas9 from S.pyogenes, supra) over 10 contiguous amino acids in a HNH nuclease domainof the site-directed polypeptide. In some embodiments, the site-directedpolypeptide comprises at most: 70, 75, 80, 85, 90, 95, 97, 99, or 100%identity to a wild-type site-directed polypeptide (e.g., Cas9 from S.pyogenes, supra) over 10 contiguous amino acids in a HNH nuclease domainof the site-directed polypeptide. In some embodiments, the site-directedpolypeptide comprises at least: 70, 75, 80, 85, 90, 95, 97, 99, or 100%identity to a wild-type site-directed polypeptide (e.g., Cas9 from S.pyogenes, supra) over 10 contiguous amino acids in a RuvC nucleasedomain of the site-directed polypeptide. In some embodiments, thesite-directed polypeptide comprises at most: 70, 75, 80, 85, 90, 95, 97,99, or 100% identity to a wild-type site-directed polypeptide (e.g.,Cas9 from S. pyogenes, supra) over 10 contiguous amino acids in a RuvCnuclease domain of the site-directed polypeptide.

In some embodiments, the site-directed polypeptide comprises a modifiedform of a wild-type exemplary site-directed polypeptide. In someembodiments, the modified form of the wild-type exemplary site-directedpolypeptide comprises a mutation that reduces the nucleic acid-cleavingactivity of the site-directed polypeptide. In some embodiments, themodified form of the wild-type exemplary site-directed polypeptide hasless than 90%, less than 80%, less than 70%, less than 60%, less than50%, less than 40%, less than 30%, less than 20%, less than 10%, lessthan 5%, or less than 1% of the nucleic acid-cleaving activity of thewild-type exemplary site-directed polypeptide (e.g., Cas9 from S.pyogenes, supra). In some embodiments, the modified form of thesite-directed polypeptide has no substantial nucleic acid-cleavingactivity. When a site-directed polypeptide is a modified form that hasno substantial nucleic acid-cleaving activity, it is referred to hereinas “enzymatically inactive.”

In some embodiments, the modified form of the site-directed polypeptidecomprises a mutation such that it can induce a single-strand break (SSB)on a target nucleic acid (e.g., by cutting only one of thesugar-phosphate backbones of a double-strand target nucleic acid). Insome embodiments, the mutation results in less than 90%, less than 80%,less than 70%, less than 60%, less than 50%, less than 40%, less than30%, less than 20%, less than 10%, less than 5%, or less than 1% of thenucleic acid-cleaving activity in one or more of the plurality ofnucleic acid-cleaving domains of the wild-type site directed polypeptide(e.g., Cas9 from S. pyogenes, supra). In some embodiments, the mutationresults in one or more of the plurality of nucleic acid-cleaving domainsretaining the ability to cleave the complementary strand of the targetnucleic acid, but reducing its ability to cleave the non-complementarystrand of the target nucleic acid. In some embodiments, the mutationresults in one or more of the plurality of nucleic acid-cleaving domainsretaining the ability to cleave the non-complementary strand of thetarget nucleic acid, but reducing its ability to cleave thecomplementary strand of the target nucleic acid. For example, residuesin the wild-type exemplary S. pyogenes Cas9 polypeptide, such as Asp10,His840, Asn854 and Asn856, are mutated to inactivate one or more of theplurality of nucleic acid-cleaving domains (e.g., nuclease domains). Theresidues to be mutated can correspond to residues Asp10, His840, Asn854and Asn856 in the wild-type exemplary S. pyogenes Cas9 polypeptide(e.g., as determined by sequence and/or structural alignment).Non-limiting examples of mutations include D10A, H840A, N854A or N856A.One skilled in the art will recognize that mutations other than alaninesubstitutions can be suitable.

In some embodiments, a D10A mutation is combined with one or more ofH840A, N854A, or N856A mutations to produce a site-directed polypeptidesubstantially lacking DNA cleavage activity. In some embodiments, aH840A mutation is combined with one or more of D10A, N854A, or N856Amutations to produce a site-directed polypeptide substantially lackingDNA cleavage activity. In some embodiments, a N854A mutation is combinedwith one or more of H840A, D10A, or N856A mutations to produce asite-directed polypeptide substantially lacking DNA cleavage activity.In some embodiments, a N856A mutation is combined with one or more ofH840A, N854A, or D10A mutations to produce a site-directed polypeptidesubstantially lacking DNA cleavage activity. Site-directed polypeptidesthat comprise one substantially inactive nuclease domain are referred toas “nickases”.

Nickase variants of RNA-guided endonucleases, for example Cas9, can beused to increase the specificity of CRISPR-mediated genome editing. Wildtype Cas9 is typically guided by a single guide RNA designed tohybridize with a specified ˜20 nucleotide sequence in the targetsequence (such as an endogenous genomic locus). However, severalmismatches can be tolerated between the guide RNA and the target locus,effectively reducing the length of required homology in the target siteto, for example, as little as 13 nt of homology, and thereby resultingin elevated potential for binding and double-strand nucleic acidcleavage by the CRISPR/Cas9 complex elsewhere in the target genome—alsoknown as off-target cleavage. Because nickase variants of Cas9 each onlycut one strand, in order to create a double-strand break it is necessaryfor a pair of nickases to bind in close proximity and on oppositestrands of the target nucleic acid, thereby creating a pair of nicks,which is the equivalent of a double-strand break. This requires that twoseparate guide RNAs—one for each nickase—must bind in close proximityand on opposite strands of the target nucleic acid. This requirementessentially doubles the minimum length of homology needed for thedouble-strand break to occur, thereby reducing the likelihood that adouble-strand cleavage event will occur elsewhere in the genome, wherethe two guide RNA sites—if they exist—are unlikely to be sufficientlyclose to each other to enable the double-strand break to form. Asdescribed in the art, nickases can also be used to promote HDR versusNHEJ. HDR can be used to introduce selected changes into target sites inthe genome through the use of specific donor sequences that effectivelymediate the desired changes. Descriptions of various CRISPR/Cas systemsfor use in gene editing can be found, e.g., in international patentapplication publication number WO2013/176772, and in NatureBiotechnology 32, 347-355 (2014), and references cited therein.

Mutations contemplated include substitutions, additions, and deletions,or any combination thereof. In some embodiments, the mutation convertsthe mutated amino acid to alanine. In some embodiments, the mutationconverts the mutated amino acid to another amino acid (e.g., glycine,serine, threonine, cysteine, valine, leucine, isoleucine, methionine,proline, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamicacid, asparagines, glutamine, histidine, lysine, or arginine). In someembodiments, the mutation converts the mutated amino acid to anon-natural amino acid (e.g., selenomethionine). In some embodiments,the mutation converts the mutated amino acid to amino acid mimics (e.g.,phosphomimics). In some embodiments, the mutation is a conservativemutation. For example, the mutation converts the mutated amino acid toamino acids that resemble the size, shape, charge, polarity,conformation, and/or rotamers of the mutated amino acids (e.g.,cysteine/serine mutation, lysine/asparagine mutation,histidine/phenylalanine mutation). In some embodiments, the mutationcauses a shift in reading frame and/or the creation of a premature stopcodon. In some embodiments, mutations cause changes to regulatoryregions of genes or loci that affect expression of one or more genes.

In some embodiments, the site-directed polypeptide (e.g., variant,mutated, enzymatically inactive and/or conditionally enzymaticallyinactive site-directed polypeptide) targets nucleic acid. In someembodiments, the site-directed polypeptide (e.g., variant, mutated,enzymatically inactive and/or conditionally enzymatically inactiveendoribonuclease) targets DNA. In some embodiments, the site-directedpolypeptide (e.g., variant, mutated, enzymatically inactive and/orconditionally enzymatically inactive endoribonuclease) targets RNA.

In some embodiments, the site-directed polypeptide comprises one or morenon-native sequences (e.g., the site-directed polypeptide is a fusionprotein).

In some embodiments, the site-directed polypeptide comprises an aminoacid sequence comprising at least 15% amino acid identity to a Cas9 froma bacterium (e.g., S. pyogenes), a nucleic acid binding domain, and twonucleic acid cleaving domains (i.e., a HNH domain and a RuvC domain).

In some embodiments, the site-directed polypeptide comprises an aminoacid sequence comprising at least 15% amino acid identity to a Cas9 froma bacterium (e.g., S. pyogenes), and two nucleic acid cleaving domains(i.e., a HNH domain and a RuvC domain).

In some embodiments, the site-directed polypeptide comprises an aminoacid sequence comprising at least 15% amino acid identity to a Cas9 froma bacterium (e.g., S. pyogenes), and two nucleic acid cleaving domains,wherein one or both of the nucleic acid cleaving domains comprise atleast 50% amino acid identity to a nuclease domain from Cas9 from abacterium (e.g., S. pyogenes).

In some embodiments, the site-directed polypeptide comprises an aminoacid sequence comprising at least 15% amino acid identity to a Cas9 froma bacterium (e.g., S. pyogenes), two nucleic acid cleaving domains(i.e., a HNH domain and a RuvC domain), and non-native sequence (forexample, a nuclear localization signal) or a linker linking thesite-directed polypeptide to a non-native sequence.

In some embodiments, the site-directed polypeptide comprises an aminoacid sequence comprising at least 15% amino acid identity to a Cas9 froma bacterium (e.g., S. pyogenes), two nucleic acid cleaving domains(i.e., a HNH domain and a RuvC domain), wherein the site-directedpolypeptide comprises a mutation in one or both of the nucleic acidcleaving domains that reduces the cleaving activity of the nucleasedomains by at least 50%.

In some embodiments, the site-directed polypeptide comprises an aminoacid sequence comprising at least 15% amino acid identity to a Cas9 froma bacterium (e.g., S. pyogenes), and two nucleic acid cleaving domains(i.e., a HNH domain and a RuvC domain), wherein one of the nucleasedomains comprises mutation of aspartic acid 10, and/or wherein one ofthe nuclease domains comprises a mutation of histidine 840, and whereinthe mutation reduces the cleaving activity of the nuclease domain(s) byat least 50%.

In some embodiments, the one or more site-directed polypeptides, e.g.DNA endonucleases, comprises two nickases that together effect onedouble-strand break at a specific locus in the genome, or four nickasesthat together effect or cause two double-strand breaks at specific lociin the genome. Alternatively, one site-directed polypeptide, e.g. DNAendonuclease, effects one double-strand break at a specific locus in thegenome.

Genome-Targeting Nucleic Acid

The present disclosure provides a genome-targeting nucleic acid that candirect the activities of an associated polypeptide (e.g., asite-directed polypeptide) to a specific target sequence within a targetnucleic acid. The genome-targeting nucleic acid can be an RNA. Agenome-targeting RNA is referred to as a “guide RNA” or “gRNA” herein. Aguide RNA comprises at least a spacer sequence that hybridizes to atarget nucleic acid sequence of interest, and a CRISPR repeat sequence.In Type II systems, the gRNA also comprises a second RNA called thetracrRNA sequence. In the Type II guide RNA (gRNA), the CRISPR repeatsequence and tracrRNA sequence hybridize to each other to form a duplex.In the Type V guide RNA (gRNA), the crRNA forms a duplex. In bothsystems, the duplex binds a site-directed polypeptide, such that theguide RNA and site-direct polypeptide form a complex. In someembodiments, the genome-targeting nucleic acid provides targetspecificity to the complex by virtue of its association with thesite-directed polypeptide. The genome-targeting nucleic acid thusdirects the activity of the site-directed polypeptide.

Exemplary guide RNAs include the spacer sequences in SEQ ID NOs: 83-158,284-408, 458-506, 699-890, 1083-1276, 1288-1298, and 1308-1312 with thegenome location of their target sequence and the associated endonuclease(e.g., Cas9) cut site. As is understood by the person of ordinary skillin the art, each guide RNA is designed to include a spacer sequencecomplementary to its genomic target sequence. For example, each of thespacer sequences in SEQ ID NOs: 83-158, 284-408, 458-506, 699-890,1083-1276, 1288-1298, and 1308-1312 can be put into a single RNA chimeraor a crRNA (along with a corresponding tracrRNA). See Jinek et al.,Science, 337, 816-821 (2012) and Deltcheva et al., Nature, 471, 602-607(2011).

In some embodiments, the genome-targeting nucleic acid is adouble-molecule guide RNA. In some embodiments, the genome-targetingnucleic acid is a single-molecule guide RNA.

A double-molecule guide RNA comprises two strands of RNA. The firststrand comprises in the 5′ to 3′ direction, an optional spacer extensionsequence, a spacer sequence and a minimum CRISPR repeat sequence. Thesecond strand comprises a minimum tracrRNA sequence (complementary tothe minimum CRISPR repeat sequence), a 3′ tracrRNA sequence and anoptional tracrRNA extension sequence.

A single-molecule guide RNA (sgRNA) in a Type II system comprises, inthe 5′ to 3′ direction, an optional spacer extension sequence, a spacersequence, a minimum CRISPR repeat sequence, a single-molecule guidelinker, a minimum tracrRNA sequence, a 3′ tracrRNA sequence and anoptional tracrRNA extension sequence. The optional tracrRNA extensionmay comprise elements that contribute additional functionality (e.g.,stability) to the guide RNA. The single-molecule guide linker links theminimum CRISPR repeat and the minimum tracrRNA sequence to form ahairpin structure. The optional tracrRNA extension comprises one or morehairpins.

A single-molecule guide RNA (sgRNA) in a Type V system comprises, in the5′ to 3′ direction, a minimum CRISPR repeat sequence and a spacersequence.

The sgRNA can comprise a 20 nucleotide spacer sequence at the 5′ end ofthe sgRNA sequence. The sgRNA can comprise a less than a 20 nucleotidespacer sequence at the 5′ end of the sgRNA sequence. The sgRNA cancomprise a more than 20 nucleotide spacer sequence at the 5′ end of thesgRNA sequence. The sgRNA can comprise a variable length spacer sequencewith 17-30 nucleotides at the 5′ end of the sgRNA sequence (see Table1).

The sgRNA can comprise no uracil at the 3′ end of the sgRNA sequence,such as in SEQ ID NO: 1 of Table 1. The sgRNA can comprise one or moreuracil at the 3′ end of the sgRNA sequence, such as in SEQ ID NOs: 1, 2,or 3 in Table 1. For example, the sgRNA can comprise 1 uracil (U) at the3′ end of the sgRNA sequence. The sgRNA can comprise 2 uracil (UU) atthe 3′ end of the sgRNA sequence. The sgRNA can comprise 3 uracil (UUU)at the 3′ end of the sgRNA sequence. The sgRNA can comprise 4 uracil(UUUU) at the 3′ end of the sgRNA sequence. The sgRNA can comprise 5uracil (UUUUU) at the 3′ end of the sgRNA sequence. The sgRNA cancomprise 6 uracil (UUUUUU) at the 3′ end of the sgRNA sequence. ThesgRNA can comprise 7 uracil (UUUUUUU) at the 3′ end of the sgRNAsequence. The sgRNA can comprise 8 uracil (UUUUUUUU) at the 3′ end ofthe sgRNA sequence.

The sgRNA can be unmodified or modified. For example, modified sgRNAscan comprise one or more 2′-O-methyl phosphorothioate nucleotides.

TABLE 1 SEQ ID NO. sgRNA sequence 1nnnnnnnnnnnnnnnnnnnnguuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccga gucggugcuuuu 2nnnnnnnnnnnnnnnnnnnnguuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccga gucggugc 3n(17-30)guuuuagagcuagaaauag caaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccgagucggugcu(1-8)

By way of illustration, guide RNAs used in the CRISPR/Cas/Cpf1 system,or other smaller RNAs can be readily synthesized by chemical means, asillustrated below and described in the art. While chemical syntheticprocedures are continually expanding, purifications of such RNAs byprocedures such as high performance liquid chromatography (HPLC, whichavoids the use of gels such as PAGE) tends to become more challenging aspolynucleotide lengths increase significantly beyond a hundred or sonucleotides. One approach used for generating RNAs of greater length isto produce two or more molecules that are ligated together. Much longerRNAs, such as those encoding a Cas9 or Cpf1 endonuclease, are morereadily generated enzymatically. Various types of RNA modifications canbe introduced during or after chemical synthesis and/or enzymaticgeneration of RNAs, e.g., modifications that enhance stability, reducethe likelihood or degree of innate immune response, and/or enhance otherattributes, as described in the art.

Spacer Extension Sequence

In some examples of genome-targeting nucleic acids, a spacer extensionsequence may modify activity, provide stability and/or provide alocation for modifications of a genome-targeting nucleic acid. A spacerextension sequence may modify on- or off-target activity or specificity.In some embodiments, a spacer extension sequence is provided. A spacerextension sequence may have a length of more than 1, 5, 10, 15, 20, 25,30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220,240, 260, 280, 300, 320, 340, 360, 380, 400, 1000, 2000, 3000, 4000,5000, 6000, or 7000 or more nucleotides. The spacer extension sequencemay have a length of less than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50,60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300,320, 340, 360, 380, 400, 1000, 2000, 3000, 4000, 5000, 6000, 7000 ormore nucleotides. In some embodiments, the spacer extension sequence isless than 10 nucleotides in length. In some embodiments, the spacerextension sequence is between 10-30 nucleotides in length. In someembodiments, the spacer extension sequence is between 30-70 nucleotidesin length.

In some embodiments, the spacer extension sequence comprises anothermoiety (e.g., a stability control sequence, an endoribonuclease bindingsequence, a ribozyme). In some embodiments, the moiety decreases orincreases the stability of a nucleic acid targeting nucleic acid. Insome embodiments, the moiety is a transcriptional terminator segment(i.e., a transcription termination sequence). In some embodiments, themoiety functions in a eukaryotic cell. In some embodiments, the moietyfunctions in a prokaryotic cell. In some embodiments, the moietyfunctions in both eukaryotic and prokaryotic cells. Non-limitingexamples of suitable moieties include: a 5′ cap (e.g., a7-methylguanylate cap (m7 G)), a riboswitch sequence (e.g., to allow forregulated stability and/or regulated accessibility by proteins andprotein complexes), a sequence that forms a dsRNA duplex (i.e., ahairpin), a sequence that targets the RNA to a subcellular location(e.g., nucleus, mitochondria, chloroplasts, and the like), amodification or sequence that provides for tracking (e.g., directconjugation to a fluorescent molecule, conjugation to a moiety thatfacilitates fluorescent detection, a sequence that allows forfluorescent detection, etc.), and/or a modification or sequence thatprovides a binding site for proteins (e.g., proteins that act on DNA,including transcriptional activators, transcriptional repressors, DNAmethyltransferases, DNA demethylases, histone acetyltransferases,histone deacetylases, and the like).

Spacer Sequence

A gRNA comprises a spacer sequence. A spacer sequence is a sequence(e.g., a 20 base pair sequence) that defines the target sequence (e.g.,a DNA target sequences, such as a genomic target sequence) of a targetnucleic acid of interest. The “target sequence” is adjacent to a PAMsequence and is the sequence modified by an RNA-guided nuclease (e.g.,Cas9). The “target nucleic acid” is a double-stranded molecule: onestrand comprises the target sequence and is referred to as the “PAMstrand,” and the other complementary strand is referred to as the“non-PAM strand.” One of skill in the art recognizes that the gRNAspacer sequence hybridizes to the reverse complement of the targetsequence, which is located in the non-PAM strand of the target nucleicacid of interest. Thus, the gRNA spacer sequence is the RNA equivalentof the target sequence. For example, if the target sequence is5′-AGAGCAACAGTGCTGTGGCC-3′ (SEQ ID NO: 76), then the gRNA spacersequence is 5′-AGAGCAACAGUGCUGUGGCC-3′ (SEQ ID NO: 152). The spacer of agRNA interacts with a target nucleic acid of interest in asequence-specific manner via hybridization (i.e., base pairing). Thenucleotide sequence of the spacer thus varies depending on the targetsequence of the target nucleic acid of interest.

In a CRISPR/Cas system herein, the spacer sequence is designed tohybridize to a region of the target nucleic acid that is located 5′ of aPAM of the Cas9 enzyme used in the system. The spacer may perfectlymatch the target sequence or may have mismatches. Each Cas9 enzyme has aparticular PAM sequence that it recognizes in a target DNA. For example,S. pyogenes recognizes in a target nucleic acid a PAM that comprises thesequence 5′-NRG-3′, where R comprises either A or G, where N is anynucleotide and N is immediately 3′ of the target nucleic acid sequencetargeted by the spacer sequence.

In some embodiments, the target nucleic acid sequence comprises 20nucleotides. In some embodiments, the target nucleic acid comprises lessthan 20 nucleotides. In some embodiments, the target nucleic acidcomprises more than 20 nucleotides. In some embodiments, the targetnucleic acid comprises at least: 5, 10, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 30 or more nucleotides. In some embodiments, the targetnucleic acid comprises at most: 5, 10, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 30 or more nucleotides. In some embodiments, the targetnucleic acid sequence comprises 20 bases immediately 5′ of the firstnucleotide of the PAM. For example, in a sequence comprising5′-NNNNNNNNNNNNNNNNNNNNNRG-3′, the target nucleic acid comprises thesequence that corresponds to the Ns, wherein N is any nucleotide, andthe underlined NRG sequence is the S. pyogenes PAM.

In some embodiments, the spacer sequence that hybridizes to the targetnucleic acid has a length of at least about 6 nucleotides (nt). Thespacer sequence can be at least about 6 nt, at least about 10 nt, atleast about 15 nt, at least about 18 nt, at least about 19 nt, at leastabout 20 nt, at least about 25 nt, at least about 30 nt, at least about35 nt or at least about 40 nt, from about 6 nt to about 80 nt, fromabout 6 nt to about 50 nt, from about 6 nt to about 45 nt, from about 6nt to about 40 nt, from about 6 nt to about 35 nt, from about 6 nt toabout 30 nt, from about 6 nt to about 25 nt, from about 6 nt to about 20nt, from about 6 nt to about 19 nt, from about 10 nt to about 50 nt,from about 10 nt to about 45 nt, from about 10 nt to about 40 nt, fromabout 10 nt to about 35 nt, from about 10 nt to about 30 nt, from about10 nt to about 25 nt, from about 10 nt to about 20 nt, from about 10 ntto about 19 nt, from about 19 nt to about 25 nt, from about 19 nt toabout 30 nt, from about 19 nt to about 35 nt, from about 19 nt to about40 nt, from about 19 nt to about 45 nt, from about 19 nt to about 50 nt,from about 19 nt to about 60 nt, from about 20 nt to about 25 nt, fromabout 20 nt to about 30 nt, from about 20 nt to about 35 nt, from about20 nt to about 40 nt, from about 20 nt to about 45 nt, from about 20 ntto about 50 nt, or from about 20 nt to about 60 nt. In some embodiments,the spacer sequence comprises 20 nucleotides. In some embodiments, thespacer comprises 19 nucleotides.

In some embodiments, the percent complementarity between the spacersequence and the target nucleic acid is at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 65%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, at least about 95%, at least about 97%,at least about 98%, at least about 99%, or 100%. In some embodiments,the percent complementarity between the spacer sequence and the targetnucleic acid is at most about 30%, at most about 40%, at most about 50%,at most about 60%, at most about 65%, at most about 70%, at most about75%, at most about 80%, at most about 85%, at most about 90%, at mostabout 95%, at most about 97%, at most about 98%, at most about 99%, or100%. In some embodiments, the percent complementarity between thespacer sequence and the target nucleic acid is 100% over the sixcontiguous 5′-most nucleotides of the target sequence of thecomplementary strand of the target nucleic acid. In some embodiments,the percent complementarity between the spacer sequence and the targetnucleic acid is at least 60% over about 20 contiguous nucleotides. Insome embodiments, the length of the spacer sequence and the targetnucleic acid differs by 1 to 6 nucleotides, which may be thought of as abulge or bulges.

In some embodiments, the spacer sequence can be designed using acomputer program. The computer program can use variables, such aspredicted melting temperature, secondary structure formation, predictedannealing temperature, sequence identity, genomic context, chromatinaccessibility, % GC, frequency of genomic occurrence (e.g., of sequencesthat are identical or are similar but vary in one or more spots as aresult of mismatch, insertion or deletion), methylation status, presenceof SNPs, and the like.

Minimum CRISPR Repeat Sequence

In some embodiments, a minimum CRISPR repeat sequence is a sequence withat least about 30%, about 40%, about 50%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 90%, about 95%, or 100%sequence identity to a reference CRISPR repeat sequence (e.g., crRNAfrom S. pyogenes).

A minimum CRISPR repeat sequence comprises nucleotides that canhybridize to a minimum tracrRNA sequence in a cell. The minimum CRISPRrepeat sequence and a minimum tracrRNA sequence form a duplex, i.e. abase-paired double-stranded structure. Together, the minimum CRISPRrepeat sequence and the minimum tracrRNA sequence bind to thesite-directed polypeptide. At least a part of the minimum CRISPR repeatsequence hybridizes to the minimum tracrRNA sequence. In someembodiments, at least a part of the minimum CRISPR repeat sequencecomprises at least about 30%, about 40%, about 50%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,or 100% complementary to the minimum tracrRNA sequence. In someembodiments, at least a part of the minimum CRISPR repeat sequencecomprises at most about 30%, about 40%, about 50%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or100% complementary to the minimum tracrRNA sequence.

The minimum CRISPR repeat sequence can have a length from about 7nucleotides to about 100 nucleotides. For example, the length of theminimum CRISPR repeat sequence is from about 7 nucleotides (nt) to about50 nt, from about 7 nt to about 40 nt, from about 7 nt to about 30 nt,from about 7 nt to about 25 nt, from about 7 nt to about 20 nt, fromabout 7 nt to about 15 nt, from about 8 nt to about 40 nt, from about 8nt to about 30 nt, from about 8 nt to about 25 nt, from about 8 nt toabout 20 nt, from about 8 nt to about 15 nt, from about 15 nt to about100 nt, from about 15 nt to about 80 nt, from about 15 nt to about 50nt, from about 15 nt to about 40 nt, from about 15 nt to about 30 nt, orfrom about 15 nt to about 25 nt. In some embodiments, the minimum CRISPRrepeat sequence is approximately 9 nucleotides in length. In someembodiments, the minimum CRISPR repeat sequence is approximately 12nucleotides in length.

In some embodiments, the minimum CRISPR repeat sequence is at leastabout 60% identical to a reference minimum CRISPR repeat sequence (e.g.,wild-type crRNA from S. pyogenes) over a stretch of at least 6, 7, or 8contiguous nucleotides. For example, the minimum CRISPR repeat sequenceis at least about 65% identical, at least about 70% identical, at leastabout 75% identical, at least about 80% identical, at least about 85%identical, at least about 90% identical, at least about 95% identical,at least about 98% identical, at least about 99% identical or 100%identical to a reference minimum CRISPR repeat sequence over a stretchof at least 6, 7, or 8 contiguous nucleotides.

Minimum tracrRNA Sequence

In some embodiments, a minimum tracrRNA sequence is a sequence with atleast about 30%, about 40%, about 50%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, or 100% sequenceidentity to a reference tracrRNA sequence (e.g., wild type tracrRNA fromS. pyogenes).

A minimum tracrRNA sequence comprises nucleotides that hybridize to aminimum CRISPR repeat sequence in a cell. A minimum tracrRNA sequenceand a minimum CRISPR repeat sequence form a duplex, i.e. a base-paireddouble-stranded structure. Together, the minimum tracrRNA sequence andthe minimum CRISPR repeat bind to a site-directed polypeptide. At leasta part of the minimum tracrRNA sequence can hybridize to the minimumCRISPR repeat sequence. In some embodiments, the minimum tracrRNAsequence is at least about 30%, about 40%, about 50%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,or 100% complementary to the minimum CRISPR repeat sequence.

The minimum tracrRNA sequence can have a length from about 7 nucleotidesto about 100 nucleotides. For example, the minimum tracrRNA sequence canbe from about 7 nucleotides (nt) to about 50 nt, from about 7 nt toabout 40 nt, from about 7 nt to about 30 nt, from about 7 nt to about 25nt, from about 7 nt to about 20 nt, from about 7 nt to about 15 nt, fromabout 8 nt to about 40 nt, from about 8 nt to about 30 nt, from about 8nt to about 25 nt, from about 8 nt to about 20 nt, from about 8 nt toabout 15 nt, from about 15 nt to about 100 nt, from about 15 nt to about80 nt, from about 15 nt to about 50 nt, from about 15 nt to about 40 nt,from about 15 nt to about 30 nt or from about 15 nt to about 25 nt long.In some embodiments, the minimum tracrRNA sequence is approximately 9nucleotides in length. In some embodiments, the minimum tracrRNAsequence is approximately 12 nucleotides. In some embodiments, theminimum tracrRNA consists of tracrRNA nt 23-48 described in Jinek etal., supra.

In some embodiments, the minimum tracrRNA sequence is at least about 60%identical to a reference minimum tracrRNA (e.g., wild type, tracrRNAfrom S. pyogenes) sequence over a stretch of at least 6, 7, or 8contiguous nucleotides. For example, the minimum tracrRNA sequence is atleast about 65% identical, about 70% identical, about 75% identical,about 80% identical, about 85% identical, about 90% identical, about 95%identical, about 98% identical, about 99% identical or 100% identical toa reference minimum tracrRNA sequence over a stretch of at least 6, 7,or 8 contiguous nucleotides.

In some embodiments, the duplex between the minimum CRISPR RNA and theminimum tracrRNA comprises a double helix. In some embodiments, theduplex between the minimum CRISPR RNA and the minimum tracrRNA comprisesat least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more nucleotides. Insome embodiments, the duplex between the minimum CRISPR RNA and theminimum tracrRNA comprises at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 or more nucleotides.

In some embodiments, the duplex comprises a mismatch (i.e., the twostrands of the duplex are not 100% complementary). In some embodiments,the duplex comprises at least about 1, 2, 3, 4, or 5 or mismatches. Insome embodiments, the duplex comprises at most about 1, 2, 3, 4, or 5 ormismatches. In some embodiments, the duplex comprises no more than 2mismatches.

Bulges

In some embodiments, there is a “bulge” in the duplex between theminimum CRISPR RNA and the minimum tracrRNA. A bulge is an unpairedregion of nucleotides within the duplex. In some embodiments, the bulgecontributes to the binding of the duplex to the site-directedpolypeptide. In some embodiments, the bulge comprises, on one side ofthe duplex, an unpaired 5′-XXXY-3′ where X is any purine and Y comprisesa nucleotide that can form a wobble pair with a nucleotide on theopposite strand, and an unpaired nucleotide region on the other side ofthe duplex. The number of unpaired nucleotides on the two sides of theduplex can be different.

In some embodiments, the bulge comprises an unpaired purine (e.g.,adenine) on the minimum CRISPR repeat strand of the bulge. In someembodiments, the bulge comprises an unpaired 5′-AAGY-3′ of the minimumtracrRNA sequence strand of the bulge, where Y comprises a nucleotidethat can form a wobble pairing with a nucleotide on the minimum CRISPRrepeat strand.

In some embodiments, a bulge on the minimum CRISPR repeat side of theduplex comprises at least 1, 2, 3, 4, or 5 or more unpaired nucleotides.In some embodiments, a bulge on the minimum CRISPR repeat side of theduplex comprises at most 1, 2, 3, 4, or 5 or more unpaired nucleotides.In some embodiments, a bulge on the minimum CRISPR repeat side of theduplex comprises 1 unpaired nucleotide.

In some embodiments, a bulge on the minimum tracrRNA sequence side ofthe duplex comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or moreunpaired nucleotides. In some embodiments, a bulge on the minimumtracrRNA sequence side of the duplex comprises at most 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 or more unpaired nucleotides. In some embodiments, abulge on a second side of the duplex (e.g., the minimum tracrRNAsequence side of the duplex) comprises 4 unpaired nucleotides.

In some embodiments, a bulge comprises at least one wobble pairing. Insome embodiments, a bulge comprises at most one wobble pairing. In someembodiments, a bulge comprises at least one purine nucleotide. In someembodiments, a bulge comprises at least 3 purine nucleotides. In someembodiments, a bulge sequence comprises at least 5 purine nucleotides.In some embodiments, a bulge sequence comprises at least one guaninenucleotide. In some embodiments, a bulge sequence comprises at least oneadenine nucleotide.

Hairpins

In various embodiments, one or more hairpins are located 3′ to theminimum tracrRNA in the 3′ tracrRNA sequence.

In some embodiments, the hairpin starts at least about 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 15, or 20 or more nucleotides 3′ from the last pairednucleotide in the minimum CRISPR repeat and minimum tracrRNA sequenceduplex. In some embodiments, the hairpin starts at most about 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 or more nucleotides 3′ of the last pairednucleotide in the minimum CRISPR repeat and minimum tracrRNA sequenceduplex.

In some embodiments, the hairpin comprises at least about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 15, or 20 or more consecutive nucleotides. In someembodiments, the hairpin comprises at most about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 15, or more consecutive nucleotides.

In some embodiments, the hairpin comprises a CC dinucleotide (i.e., twoconsecutive cytosine nucleotides).

In some embodiments, the hairpin comprises duplexed nucleotides (e.g.,nucleotides in a hairpin, hybridized together). For example, a hairpincomprises a CC dinucleotide that is hybridized to a GG dinucleotide in ahairpin duplex of the 3′ tracrRNA sequence.

One or more of the hairpins can interact with guide RNA-interactingregions of a site-directed polypeptide.

In some embodiments, there are two or more hairpins, and in otherembodiments there are three or more hairpins.

3′ tracrRNA Sequence

In some embodiments, a 3′ tracrRNA sequence comprises a sequence with atleast about 30%, about 40%, about 50%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, or 100% sequenceidentity to a reference tracrRNA sequence (e.g., a tracrRNA from S.pyogenes).

The 3′ tracrRNA sequence has a length from about 6 nucleotides to about100 nucleotides. For example, the 3′ tracrRNA sequence can have a lengthfrom about 6 nucleotides (nt) to about 50 nt, from about 6 nt to about40 nt, from about 6 nt to about 30 nt, from about 6 nt to about 25 nt,from about 6 nt to about 20 nt, from about 6 nt to about 15 nt, fromabout 8 nt to about 40 nt, from about 8 nt to about 30 nt, from about 8nt to about 25 nt, from about 8 nt to about 20 nt, from about 8 nt toabout 15 nt, from about 15 nt to about 100 nt, from about 15 nt to about80 nt, from about 15 nt to about 50 nt, from about 15 nt to about 40 nt,from about 15 nt to about 30 nt, or from about 15 nt to about 25 nt. Insome embodiments, the 3′ tracrRNA sequence has a length of approximately14 nucleotides.

In some embodiments, the 3′ tracrRNA sequence is at least about 60%identical to a reference 3′ tracrRNA sequence (e.g., wild type 3′tracrRNA sequence from S. pyogenes) over a stretch of at least 6, 7, or8 contiguous nucleotides. For example, the 3′ tracrRNA sequence is atleast about 60% identical, about 65% identical, about 70% identical,about 75% identical, about 80% identical, about 85% identical, about 90%identical, about 95% identical, about 98% identical, about 99%identical, or 100% identical, to a reference 3′ tracrRNA sequence (e.g.,wild type 3′ tracrRNA sequence from S. pyogenes) over a stretch of atleast 6, 7, or 8 contiguous nucleotides.

In some embodiments, the 3′ tracrRNA sequence comprises more than oneduplexed region (e.g., hairpin, hybridized region). In some embodiments,the 3′ tracrRNA sequence comprises two duplexed regions.

In some embodiments, the 3′ tracrRNA sequence comprises a stem loopstructure. In some embodiments, the stem loop structure in the 3′tracrRNA comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 or 20 ormore nucleotides. In some embodiments, the stem loop structure in the 3′tracrRNA comprises at most 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or morenucleotides. In some embodiments, the stem loop structure comprises afunctional moiety. For example, the stem loop structure may comprise anaptamer, a ribozyme, a protein-interacting hairpin, a CRISPR array, anintron, or an exon. In some embodiments, the stem loop structurecomprises at least about 1, 2, 3, 4, or 5 or more functional moieties.In some embodiments, the stem loop structure comprises at most about 1,2, 3, 4, or 5 or more functional moieties.

In some embodiments, the hairpin in the 3′ tracrRNA sequence comprises aP-domain. In some embodiments, the P-domain comprises a double-strandedregion in the hairpin.

tracrRNA Extension Sequence

In some embodiments, a tracrRNA extension sequence is provided whetherthe tracrRNA is in the context of single-molecule guides ordouble-molecule guides. In some embodiments, the tracrRNA extensionsequence has a length from about 1 nucleotide to about 400 nucleotides.In some embodiments, the tracrRNA extension sequence has a length ofmore than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100,120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, or400 nucleotides. In some embodiments, the tracrRNA extension sequencehas a length from about 20 to about 5000 or more nucleotides. In someembodiments, the tracrRNA extension sequence has a length of more than1000 nucleotides. In some embodiments, the tracrRNA extension sequencehas a length of less than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60,70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320,340, 360, 380, 400 or more nucleotides. In some embodiments, thetracrRNA extension sequence has a length of less than 1000 nucleotides.In some embodiments, the tracrRNA extension sequence comprises less than10 nucleotides in length. In some embodiments, the tracrRNA extensionsequence is 10-30 nucleotides in length. In some embodiments, thetracrRNA extension sequence is 30-70 nucleotides in length.

In some embodiments, the tracrRNA extension sequence comprises afunctional moiety (e.g., a stability control sequence, ribozyme,endoribonuclease binding sequence). In some embodiments, the functionalmoiety comprises a transcriptional terminator segment (i.e., atranscription termination sequence). In some embodiments, the functionalmoiety has a total length from about 10 nucleotides (nt) to about 100nucleotides, from about 10 nt to about 20 nt, from about 20 nt to about30 nt, from about 30 nt to about 40 nt, from about 40 nt to about 50 nt,from about 50 nt to about 60 nt, from about 60 nt to about 70 nt, fromabout 70 nt to about 80 nt, from about 80 nt to about 90 nt, or fromabout 90 nt to about 100 nt, from about 15 nt to about 80 nt, from about15 nt to about 50 nt, from about 15 nt to about 40 nt, from about 15 ntto about 30 nt, or from about 15 nt to about 25 nt. In some embodiments,the functional moiety functions in a eukaryotic cell. In someembodiments, the functional moiety functions in a prokaryotic cell. Insome embodiments, the functional moiety functions in both eukaryotic andprokaryotic cells.

Non-limiting examples of suitable tracrRNA extension functional moietiesinclude a 3′ poly-adenylated tail, a riboswitch sequence (e.g., to allowfor regulated stability and/or regulated accessibility by proteins andprotein complexes), a sequence that forms a dsRNA duplex (i.e., ahairpin), a sequence that targets the RNA to a subcellular location(e.g., nucleus, mitochondria, chloroplasts, and the like), amodification or sequence that provides for tracking (e.g., directconjugation to a fluorescent molecule, conjugation to a moiety thatfacilitates fluorescent detection, a sequence that allows forfluorescent detection, etc.), and/or a modification or sequence thatprovides a binding site for proteins (e.g., proteins that act on DNA,including transcriptional activators, transcriptional repressors, DNAmethyltransferases, DNA demethylases, histone acetyltransferases,histone deacetylases, and the like). In some embodiments, the tracrRNAextension sequence comprises a primer binding site or a molecular index(e.g., barcode sequence). In some embodiments, the tracrRNA extensionsequence comprises one or more affinity tags.

Single-Molecule Guide Linker Sequence

In some embodiments, the linker sequence of a single-molecule guidenucleic acid has a length from about 3 nucleotides to about 100nucleotides. In Jinek et al., supra, for example, a simple 4 nucleotide“tetraloop” (-GAAA-) was used, Science, 337(6096):816-821 (2012). Anillustrative linker has a length from about 3 nucleotides (nt) to about90 nt, from about 3 nt to about 80 nt, from about 3 nt to about 70 nt,from about 3 nt to about 60 nt, from about 3 nt to about 50 nt, fromabout 3 nt to about 40 nt, from about 3 nt to about 30 nt, from about 3nt to about 20 nt, from about 3 nt to about 10 nt. For example, thelinker can have a length from about 3 nt to about 5 nt, from about 5 ntto about 10 nt, from about 10 nt to about 15 nt, from about 15 nt toabout 20 nt, from about 20 nt to about 25 nt, from about 25 nt to about30 nt, from about 30 nt to about 35 nt, from about 35 nt to about 40 nt,from about 40 nt to about 50 nt, from about 50 nt to about 60 nt, fromabout 60 nt to about 70 nt, from about 70 nt to about 80 nt, from about80 nt to about 90 nt, or from about 90 nt to about 100 nt. In someembodiments, the linker of a single-molecule guide nucleic acid isbetween 4 and 40 nucleotides. In some embodiments, the linker is atleast about 100, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500,5000, 5500, 6000, 6500, or 7000 or more nucleotides. In someembodiments, the linker is at most about 100, 500, 1000, 1500, 2000,2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, or 7000 or morenucleotides.

Linkers comprise any of a variety of sequences, although in someexamples the linker will not comprise sequences that have extensiveregions of homology with other portions of the guide RNA, which mightcause intramolecular binding that could interfere with other functionalregions of the guide. In Jinek et al., supra, a simple 4 nucleotidesequence -GAAA- was used, Science, 337(6096):816-821 (2012), butnumerous other sequences, including longer sequences can likewise beused.

In some embodiments, the linker sequence comprises a functional moiety.For example, the linker sequence may comprise one or more features,including an aptamer, a ribozyme, a protein-interacting hairpin, aprotein binding site, a CRISPR array, an intron, or an exon. In someembodiments, the linker sequence comprises at least about 1, 2, 3, 4, or5 or more functional moieties. In some embodiments, the linker sequencecomprises at most about 1, 2, 3, 4, or 5 or more functional moieties.

Genome Engineering Strategies to Edit Cells by Deletion, Insertion, orModulation of One or More Nucleic Acids or Exons within or Near a TargetGene, and by Knocking-in cDNA, an Expression Vector, or Minigene intothe Locus of the Corresponding Target Gene

Some genome engineering strategies involve deleting the target DNAand/or knocking-in cDNA, expression vector, or a minigene (comprised ofone or more exons and introns or natural or synthetic introns) and/orknocking-in a cDNA interrupted by some or all target introns into thelocus of the corresponding gene. These strategies treat, and/or mitigatethe diseased state. These strategies may require a more custom approach.This is advantageous, as HDR efficiencies may be inversely related tothe size of the donor molecule. Also, it is expected that the donortemplates can fit into size constrained viral vector molecules, e.g.,adeno-associated virus (AAV) molecules, which have been shown to be aneffective means of donor template delivery. Also, it is expected thatthe donor templates can fit into other size constrained molecules,including, by way of non-limiting example, platelets and/or exosomes orother microvesicles.

Homology direct repair is a cellular mechanism for repairingdouble-stranded breaks (DSBs). The most common form is homologousrecombination. There are additional pathways for HDR, includingsingle-strand annealing and alternative-HDR. Genome engineering toolsallow researchers to manipulate the cellular homologous recombinationpathways to create site-specific modifications to the genome. It hasbeen found that cells can repair a double-stranded break using asynthetic donor molecule provided in trans. Therefore, by introducing adouble-stranded break near a specific mutation and providing a suitabledonor, targeted changes can be made in the genome. Specific cleavageincreases the rate of HDR more than 1,000 fold above the rate of 1 in10⁶ cells receiving a homologous donor alone. The rate of homologydirected repair (HDR) at a particular nucleotide is a function of thedistance to the cut site, so choosing overlapping or nearest targetsites is important. Gene editing offers the advantage over geneaddition, as correcting in situ leaves the rest of the genomeunperturbed.

Supplied donors for editing by HDR vary markedly but generally containthe intended sequence with small or large flanking homology arms toallow annealing to the genomic DNA. The homology regions flanking theintroduced genetic changes can be 30 bp or smaller or as large as amulti-kilobase cassette that can contain promoters, cDNAs, etc. Bothsingle-stranded and double-stranded oligonucleotide donors have beenused. These oligonucleotides range in size from less than 100 nt to overmany kb, though longer ssDNA can also be generated and used.Double-stranded donors are often used, including PCR amplicons,plasmids, and mini-circles. In general, it has been found that an AAVvector is a very effective means of delivery of a donor template, thoughthe packaging limits for individual donors is <5 kb. Activetranscription of the donor increased HDR three-fold, indicating theinclusion of promoter may increase conversion. Conversely, CpGmethylation of the donor decreased gene expression and HDR.

In addition to wildtype endonucleases, such as Cas9, nickase variantsexist that have one or the other nuclease domain inactivated resultingin cutting of only one DNA strand. HDR can be directed from individualCas nickases or using pairs of nickases that flank the target area.Donors can be single-stranded, nicked, or dsDNA.

The donor DNA can be supplied with the nuclease or independently by avariety of different methods, for example by transfection,nano-particle, micro-injection, or viral transduction. A range oftethering options has been proposed to increase the availability of thedonors for HDR. Examples include attaching the donor to the nuclease,attaching to DNA binding proteins that bind nearby, or attaching toproteins that are involved in DNA end binding or repair.

The repair pathway choice can be guided by a number of cultureconditions, such as those that influence cell cycling, or by targetingof DNA repair and associated proteins. For example, to increase HDR, keyNHEJ molecules can be suppressed, such as KU70, KU80 or DNA ligase IV.

Without a donor present, the ends from a DNA break or ends fromdifferent breaks can be joined using the several nonhomologous repairpathways in which the DNA ends are joined with little or no base-pairingat the junction. In addition to canonical NHEJ, there are similar repairmechanisms, such as alt-NHEJ. If there are two breaks, the interveningsegment can be deleted or inverted. NHEJ repair pathways can lead toinsertions, deletions or mutations at the joints.

NHEJ was used to insert a gene expression cassette into a defined locusin human cell lines after nuclease cleavage of both the chromosome andthe donor molecule. (Cristea, et al., Biotechnology and Bioengineering110:871-880 (2012); Maresca, M., Lin, V. G., Guo, N. & Yang, Y., GenomeRes 23, 539-546 (2013)).

In addition to genome editing by NHEJ or HDR, site-specific geneinsertions have been conducted that use both the NHEJ pathway and HR. Acombination approach may be applicable in certain settings, possiblyincluding intron/exon borders. NHEJ may prove effective for ligation inthe intron, while the error-free HDR may be better suited in the codingregion.

The target gene contains a number of exons. Any one or more of the exonsor nearby introns may be targeted. Alternatively, there are variousmutations associated with various medical conditions, which are acombination of insertions, deletions, missense, nonsense, frameshift andother mutations, with the common effect of inactivating target. Any oneor more of the mutations may be repaired in order to restore theinactive target. As a further alternative, a cDNA construct, expressionvector, or minigene (comprised of, natural or synthetic enhancer andpromoter, one or more exons, and natural or synthetic introns, andnatural or synthetic 3′UTR and polyadenylation signal) may be knocked-into the genome or a target gene. In some embodiments, the methods canprovide one gRNA or a pair of gRNAs that can be used to facilitateincorporation of a new sequence from a polynucleotide donor template toknock-in a cDNA construct, expression vector, or minigene

Some embodiments of the methods provide gRNA pairs that make a deletionby cutting the gene twice, one gRNA cutting at the 5′ end of one or moremutations and the other gRNA cutting at the 3′ end of one or moremutations that facilitates insertion of a new sequence from apolynucleotide donor template to replace the one or more mutations, ordeletion may exclude mutant amino acids or amino acids adjacent to it(e.g., premature stop codon) and lead to expression of a functionalprotein, or restore an open reading frame. The cutting may beaccomplished by a pair of DNA endonucleases that each makes a DSB in thegenome, or by multiple nickases that together make a DSB in the genome.

Alternatively, some embodiments of the methods provide one gRNA to makeone double-strand cut around one or more mutations that facilitatesinsertion of a new sequence from a polynucleotide donor template toreplace the one or more mutations. The double-strand cut may be made bya single DNA endonuclease or multiple nickases that together make a DSBin the genome, or single gRNA may lead to deletion (MMEJ), which mayexclude mutant amino acid (e.g., premature stop codon) and lead toexpression of a functional protein, or restore an open reading frame.

Illustrative modifications within the target gene include replacementswithin or near (proximal) to the mutations referred to above, such aswithin the region of less than 3 kb, less than 2 kb, less than 1 kb,less than 0.5 kb upstream or downstream of the specific mutation. Giventhe relatively wide variations of mutations in the target gene, it willbe appreciated that numerous variations of the replacements referencedabove (including without limitation larger as well as smallerdeletions), would be expected to result in restoration of the targetgene.

Such variants include replacements that are larger in the 5′ and/or 3′direction than the specific mutation in question, or smaller in eitherdirection. Accordingly, by “near” or “proximal” with respect to specificreplacements, it is intended that the SSB or DSB locus associated with adesired replacement boundary (also referred to herein as an endpoint)may be within a region that is less than about 3 kb from the referencelocus noted. In some embodiments, the SSB or DSB locus is more proximaland within 2 kb, within 1 kb, within 0.5 kb, or within 0.1 kb. In thecase of small replacement, the desired endpoint is at or “adjacent to”the reference locus, by which it is intended that the endpoint is within100 bp, within 50 bp, within 25 bp, or less than about 10 bp to 5 bpfrom the reference locus.

Embodiments comprising larger or smaller replacements is expected toprovide the same benefit, as long as the target protein activity isrestored. It is thus expected that many variations of the replacementsdescribed and illustrated herein will be effective for ameliorating amedical condition.

Another genome engineering strategy involves exon deletion. Targeteddeletion of specific exons is an attractive strategy for treating alarge subset of patients with a single therapeutic cocktail. Deletionscan either be single exon deletions or multi-exon deletions. Whilemulti-exon deletions can reach a larger number of patients, for largerdeletions the efficiency of deletion greatly decreases with increasedsize. Therefore, deletions range can be from 40 to 10,000 base pairs(bp) in size. For example, deletions may range from 40-100; 100-300;300-500; 500-1,000; 1,000-2,000; 2,000-3,000; 3,000-5,000; or5,000-10,000 base pairs in size.

Deletions can occur in enhancer, promoter, 1st intron, and/or 3′UTRleading to upregulation of the gene expression, and/or through deletionof the regulatory elements.

In order to ensure that the pre-mRNA is properly processed followingdeletion, the surrounding splicing signals can be deleted. Splicingdonor and acceptors are generally within 100 base pairs of theneighboring intron. Therefore, in some embodiments, methods can provideall gRNAs that cut approximately +/−100-3100 bp with respect to eachexon/intron junction of interest.

For any of the genome editing strategies, gene editing can be confirmedby sequencing or PCR analysis.

Target Sequence Selection

Shifts in the location of the 5′ boundary and/or the 3′ boundaryrelative to particular reference loci are used to facilitate or enhanceparticular applications of gene editing, which depend in part on theendonuclease system selected for the editing, as further described andillustrated herein.

In a first, nonlimiting example of such target sequence selection, manyendonuclease systems have rules or criteria that guide the initialselection of potential target sites for cleavage, such as therequirement of a PAM sequence motif in a particular position adjacent tothe DNA cleavage sites in the case of CRISPR Type II or Type Vendonucleases.

In another nonlimiting example of target sequence selection oroptimization, the frequency of off-target activity for a particularcombination of target sequence and gene editing endonuclease (i.e. thefrequency of DSBs occurring at sites other than the selected targetsequence) is assessed relative to the frequency of on-target activity.In some embodiments, cells that have been correctly edited at thedesired locus may have a selective advantage relative to other cells.Illustrative, but nonlimiting, examples of a selective advantage includethe acquisition of attributes such as enhanced rates of replication,persistence, resistance to certain conditions, enhanced rates ofsuccessful engraftment or persistence in vivo following introductioninto a patient, and other attributes associated with the maintenance orincreased numbers or viability of such cells. In other embodiments,cells that have been correctly edited at the desired locus may bepositively selected for by one or more screening methods used toidentify, sort or otherwise select for cells that have been correctlyedited. Both selective advantage and directed selection methods may takeadvantage of the phenotype associated with the correction. In someembodiments, cells may be edited two or more times in order to create asecond modification that creates a new phenotype that is used to selector purify the intended population of cells. Such a second modificationcould be created by adding a second gRNA for a selectable or screenablemarker. In some embodiments, cells can be correctly edited at thedesired locus using a DNA fragment that contains the cDNA and also aselectable marker.

Whether any selective advantage is applicable or any directed selectionis to be applied in a particular case, target sequence selection is alsoguided by consideration of off-target frequencies in order to enhancethe effectiveness of the application and/or reduce the potential forundesired alterations at sites other than the desired target. Asdescribed further and illustrated herein and in the art, the occurrenceof off-target activity is influenced by a number of factors includingsimilarities and dissimilarities between the target site and variousoff-target sites, as well as the particular endonuclease used.Bioinformatics tools are available that assist in the prediction ofoff-target activity, and frequently such tools can also be used toidentify the most likely sites of off-target activity, which can then beassessed in experimental settings to evaluate relative frequencies ofoff-target to on-target activity, thereby allowing the selection ofsequences that have higher relative on-target activities. Illustrativeexamples of such techniques are provided herein, and others are known inthe art.

Another aspect of target sequence selection relates to homologousrecombination events. Sequences sharing regions of homology can serve asfocal points for homologous recombination events that result in deletionof intervening sequences. Such recombination events occur during thenormal course of replication of chromosomes and other DNA sequences, andalso at other times when DNA sequences are being synthesized, such as inthe case of repairs of double-strand breaks (DSBs), which occur on aregular basis during the normal cell replication cycle but may also beenhanced by the occurrence of various events (such as UV light and otherinducers of DNA breakage) or the presence of certain agents (such asvarious chemical inducers). Many such inducers cause DSBs to occurindiscriminately in the genome, and DSBs are regularly being induced andrepaired in normal cells. During repair, the original sequence may bereconstructed with complete fidelity, however, in some embodiments,small insertions or deletions (referred to as “indels”) are introducedat the DSB site.

DSBs may also be specifically induced at particular locations, as in thecase of the endonucleases systems described herein, which can be used tocause directed or preferential gene modification events at selectedchromosomal locations. The tendency for homologous sequences to besubject to recombination in the context of DNA repair (as well asreplication) can be taken advantage of in a number of circumstances, andis the basis for one application of gene editing systems, such asCRISPR, in which homology directed repair is used to insert a sequenceof interest, provided through use of a “donor” polynucleotide, into adesired chromosomal location.

Regions of homology between particular sequences, which can be smallregions of “microhomology” that may comprise as few as ten basepairs orless, can also be used to bring about desired deletions. For example, asingle DSB is introduced at a site that exhibits microhomology with anearby sequence. During the normal course of repair of such DSB, aresult that occurs with high frequency is the deletion of theintervening sequence as a result of recombination being facilitated bythe DSB and concomitant cellular repair process.

In some circumstances, however, selecting target sequences withinregions of homology can also give rise to much larger deletions,including gene fusions (when the deletions are in coding regions), whichmay or may not be desired given the particular circumstances.

The examples provided herein further illustrate the selection of varioustarget regions for the creation of DSBs designed to induce replacementsthat result in modulation of target protein activity, as well as theselection of specific target sequences within such regions that aredesigned to minimize off-target events relative to on-target events.

Nucleic Acid Modifications

In some embodiments, polynucleotides introduced into cells comprise oneor more modifications that can be used individually or in combination,for example, to enhance activity, stability or specificity, alterdelivery, reduce innate immune responses in host cells, or for otherenhancements, as further described herein and known in the art.

In some embodiments, modified polynucleotides are used in theCRISPR/Cas9/Cpf1 system, in which case the guide RNAs (eithersingle-molecule guides or double-molecule guides) and/or a DNA or an RNAencoding a Cas or Cpf1 endonuclease introduced into a cell can bemodified, as described and illustrated below. Such modifiedpolynucleotides can be used in the CRISPR/Cas9/Cpf1 system to edit anyone or more genomic loci.

Using the CRISPR/Cas9/Cpf1 system for purposes of nonlimitingillustrations of such uses, modifications of guide RNAs can be used toenhance the formation or stability of the CRISPR/Cas9/Cpf1 genomeediting complex comprising guide RNAs, which may be single-moleculeguides or double-molecule, and a Cas or Cpf1 endonuclease. Modificationsof guide RNAs can also or alternatively be used to enhance theinitiation, stability or kinetics of interactions between the genomeediting complex with the target sequence in the genome, which can beused, for example, to enhance on-target activity. Modifications of guideRNAs can also or alternatively be used to enhance specificity, e.g., therelative rates of genome editing at the on-target site as compared toeffects at other (off-target) sites.

Modifications can also or alternatively be used to increase thestability of a guide RNA, e.g., by increasing its resistance todegradation by ribonucleases (RNases) present in a cell, thereby causingits half-life in the cell to be increased. Modifications enhancing guideRNA half-life can be particularly useful in aspects in which a Cas orCpf1 endonuclease is introduced into the cell to be edited via an RNAthat needs to be translated in order to generate endonuclease, becauseincreasing the half-life of guide RNAs introduced at the same time asthe RNA encoding the endonuclease can be used to increase the time thatthe guide RNAs and the encoded Cas or Cpf1 endonuclease co-exist in thecell.

Modifications can also or alternatively be used to decrease thelikelihood or degree to which RNAs introduced into cells elicit innateimmune responses. Such responses, which have been well characterized inthe context of RNA interference (RNAi), including small-interfering RNAs(siRNAs), as described below and in the art, tend to be associated withreduced half-life of the RNA and/or the elicitation of cytokines orother factors associated with immune responses.

One or more types of modifications can also be made to RNAs encoding anendonuclease that are introduced into a cell, including, withoutlimitation, modifications that enhance the stability of the RNA (such asby increasing its degradation by RNAses present in the cell),modifications that enhance translation of the resulting product (i.e.the endonuclease), and/or modifications that decrease the likelihood ordegree to which the RNAs introduced into cells elicit innate immuneresponses.

Combinations of modifications, such as the foregoing and others, canlikewise be used. In the case of CRISPR/Cas9/Cpf1, for example, one ormore types of modifications can be made to guide RNAs (including thoseexemplified above), and/or one or more types of modifications can bemade to RNAs encoding Cas endonuclease (including those exemplifiedabove).

By way of illustration, guide RNAs used in the CRISPR/Cas9/Cpf1 system,or other smaller RNAs can be readily synthesized by chemical means,enabling a number of modifications to be readily incorporated, asillustrated below and described in the art. While chemical syntheticprocedures are continually expanding, purifications of such RNAs byprocedures such as high performance liquid chromatography (HPLC, whichavoids the use of gels such as PAGE) tends to become more challenging aspolynucleotide lengths increase significantly beyond a hundred or sonucleotides. One approach used for generating chemically-modified RNAsof greater length is to produce two or more molecules that are ligatedtogether. Much longer RNAs, such as those encoding a Cas9 endonuclease,are more readily generated enzymatically. While fewer types ofmodifications are generally available for use in enzymatically producedRNAs, there are still modifications that can be used to, e.g., enhancestability, reduce the likelihood or degree of innate immune response,and/or enhance other attributes, as described further below and in theart; and new types of modifications are regularly being developed.

By way of illustration of various types of modifications, especiallythose used frequently with smaller chemically synthesized RNAs,modifications can comprise one or more nucleotides modified at the 2′position of the sugar, in some embodiments, a 2′-O-alkyl,2′-O-alkyl-O-alkyl, or 2′-fluoro-modified nucleotide. In someembodiments, RNA modifications comprise 2′-fluoro, 2′-amino or 2′O-methyl modifications on the ribose of pyrimidines, abasic residues, oran inverted base at the 3′ end of the RNA. Such modifications areroutinely incorporated into oligonucleotides and these oligonucleotideshave been shown to have a higher Tm (i.e., higher target bindingaffinity) than 2′-deoxyoligonucleotides against a given target.

A number of nucleotide and nucleoside modifications have been shown tomake the oligonucleotide into which they are incorporated more resistantto nuclease digestion than the native oligonucleotide; these modifiedoligos survive intact for a longer time than unmodifiedoligonucleotides. Specific examples of modified oligonucleotides includethose comprising modified backbones, for example, phosphorothioates,phosphotriesters, methyl phosphonates, short chain alkyl or cycloalkylintersugar linkages or short chain heteroatomic or heterocyclicintersugar linkages. Some oligonucleotides are oligonucleotides withphosphorothioate backbones and those with heteroatom backbones,particularly CH₂—NH—O—CH₂, CH, ˜N(CH₃)˜O˜CH₂ (known as amethylene(methylimino) or MMI backbone), CH₂—O—N (CH₃)—CH₂,CH₂—N(CH₃)—N(CH₃)—CH₂ and O—N(CH₃)— CH₂—CH₂ backbones, wherein thenative phosphodiester backbone is represented as O—P—O—CH); amidebackbones [see De Mesmaeker et al., Ace. Chem. Res., 28:366-374 (1995)];morpholino backbone structures (see Summerton and Weller, U.S. Pat. No.5,034,506); peptide nucleic acid (PNA) backbone (wherein thephosphodiester backbone of the oligonucleotide is replaced with apolyamide backbone, the nucleotides being bound directly or indirectlyto the aza nitrogen atoms of the polyamide backbone, see Nielsen et al.,Science 1991, 254, 1497). Phosphorus-containing linkages include, butare not limited to, phosphorothioates, chiral phosphorothioates,phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters,methyl and other alkyl phosphonates comprising 3′alkylene phosphonatesand chiral phosphonates, phosphinates, phosphoramidates comprising3′-amino phosphoramidate and aminoalkylphosphoramidates,thionophosphoramidates, thionoalkylphosphonates,thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′linkages, 2′-5′ linked analogs of these, and those having invertedpolarity wherein the adjacent pairs of nucleoside units are linked 3′-5′to 5′-3′ or 2′-5′ to 5′-2′; see U.S. Pat. Nos. 3,687,808; 4,469,863;4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019;5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496;5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306;5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050, each of whichis herein incorporated by reference.

Morpholino-based oligomeric compounds are described in Braasch and DavidCorey, Biochemistry, 41(14): 4503-4510 (2002); Genesis, Volume 30, Issue3, (2001); Heasman, Dev. Biol., 243: 209-214 (2002); Nasevicius et al.,Nat. Genet., 26:216-220 (2000); Lacerra et al., Proc. Natl. Acad. Sci.,97: 9591-9596 (2000); and U.S. Pat. No. 5,034,506, issued Jul. 23, 1991.

Cyclohexenyl nucleic acid oligonucleotide mimetics are described in Wanget al., J. Am. Chem. Soc., 122: 8595-8602 (2000).

Modified oligonucleotide backbones that do not include a phosphorus atomtherein have backbones that are formed by short chain alkyl orcycloalkyl internucleoside linkages, mixed heteroatom and alkyl orcycloalkyl internucleoside linkages, or one or more short chainheteroatomic or heterocyclic internucleoside linkages. These comprisethose having morpholino linkages (formed in part from the sugar portionof a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfonebackbones; formacetyl and thioformacetyl backbones; methylene formacetyland thioformacetyl backbones; alkene containing backbones; sulfamatebackbones; methyleneimino and methylenehydrazino backbones; sulfonateand sulfonamide backbones; amide backbones; and others having mixed N,O, S, and CH₂ component parts; see U.S. Pat. Nos. 5,034,506; 5,166,315;5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564;5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307;5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046;5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and5,677,439, each of which is herein incorporated by reference.

One or more substituted sugar moieties can also be included, e.g., oneof the following at the 2′ position: OH, SH, SCH₃, F, OCN, OCH₃, OCH₃O(CH₂)n CH₃, O(CH₂)n NH₂, or O(CH₂)n CH₃, where n is from 1 to about 10;C1 to C10 lower alkyl, alkoxyalkoxy, substituted lower alkyl, alkaryl oraralkyl; Cl; Br; CN; CF₃; OCF₃; O-, S-, or N-alkyl; O-, S-, orN-alkenyl; SOCH₃; SO₂ CH₃; ONO₂; NO₂; N₃; NH₂; heterocycloalkyl;heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl;an RNA cleaving group; a reporter group; an intercalator; a group forimproving the pharmacokinetic properties of an oligonucleotide; or agroup for improving the pharmacodynamic properties of an oligonucleotideand other substituents having similar properties. In some embodiments, amodification includes 2′-methoxyethoxy (2′-O—CH₂CH₂OCH₃, also known as2′4)-(2-methoxyethyl)) (Martin et al, HeIv. Chim Acta, 1995, 78, 486).Other modifications include 2′-methoxy (2′-O—CH₃), 2′-propoxy (2′-OCH₂CH₂CH₃) and 2′-fluoro (2′-F). Similar modifications may also be made atother positions on the oligonucleotide, particularly the 3′ position ofthe sugar on the 3′ terminal nucleotide and the 5′ position of 5′terminal nucleotide. Oligonucleotides may also have sugar mimetics, suchas cyclobutyls in place of the pentofuranosyl group.

In some embodiments, both a sugar and an internucleoside linkage, i.e.,the backbone, of the nucleotide units are replaced with novel groups.The base units are maintained for hybridization with an appropriatenucleic acid target compound. One such oligomeric compound, anoligonucleotide mimetic that has been shown to have excellenthybridization properties, is referred to as a peptide nucleic acid(PNA). In PNA compounds, the sugar-backbone of an oligonucleotide isreplaced with an amide containing backbone, for example, anaminoethylglycine backbone. The nucleobases are retained and are bounddirectly or indirectly to aza nitrogen atoms of the amide portion of thebackbone. Representative United States patents that teach thepreparation of PNA compounds comprise, but are not limited to, U.S. Pat.Nos. 5,539,082; 5,714,331; and 5,719,262. Further teaching of PNAcompounds can be found in Nielsen et al, Science, 254: 1497-1500 (1991).

Guide RNAs can also include, additionally or alternatively, nucleobase(often referred to in the art simply as “base”) modifications orsubstitutions. As used herein, “unmodified” or “natural” nucleobasesinclude adenine (A), guanine (G), thymine (T), cytosine (C), and uracil(U). Modified nucleobases include nucleobases found only infrequently ortransiently in natural nucleic acids, e.g., hypoxanthine,6-methyladenine, 5-Me pyrimidines, particularly 5-methylcytosine (alsoreferred to as 5-methyl-2′ deoxycytosine and often referred to in theart as 5-Me-C), 5-hydroxymethylcytosine (HMC), glycosyl HMC andgentobiosyl HMC, as well as synthetic nucleobases, e.g., 2-aminoadenine,2-(methylamino)adenine, 2-(imidazolylalkyl)adenine,2-(aminoalklyamino)adenine or other heterosubstituted alkyladenines,2-thiouracil, 2-thiothymine, 5-bromouracil, 5-hydroxymethyluracil,8-azaguanine, 7-deazaguanine, N6 (6-aminohexyl)adenine, and2,6-diaminopurine. Kornberg, A., DNA Replication, W. H. Freeman & Co.,San Francisco, pp 75-77 (1980); Gebeyehu et al., Nucl. Acids Res.15:4513 (1997). A “universal” base known in the art, e.g., inosine, canalso be included. 5-Me-C substitutions have been shown to increasenucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., in Crooke,S. T. and Lebleu, B., eds., Antisense Research and Applications, CRCPress, Boca Raton, 1993, pp. 276-278) and are embodiments of basesubstitutions.

Modified nucleobases comprise other synthetic and natural nucleobases,such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine,hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives ofadenine and guanine, 2-propyl and other alkyl derivatives of adenine andguanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouraciland cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine andthymine, 5-uracil (pseudo-uracil), 4-thiouracil, 8-halo, 8-amino,8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines andguanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other5-substituted uracils and cytosines, 7-methylquanine and7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and7-deazaadenine, and 3-deazaguanine and 3-deazaadenine.

Further, nucleobases comprise those disclosed in U.S. Pat. No.3,687,808, those disclosed in ‘The Concise Encyclopedia of PolymerScience And Engineering’, pages 858-859, Kroschwitz, J. I., ed. JohnWiley & Sons, 1990, those disclosed by Englisch et al., AngewandleChemie, International Edition’, 1991, 30, page 613, and those disclosedby Sanghvi, Y. S., Chapter 15, Antisense Research and Applications',pages 289-302, Crooke, S. T. and Lebleu, B. ea., CRC Press, 1993.Certain of these nucleobases are particularly useful for increasing thebinding affinity of the oligomeric compounds of the disclosure. Theseinclude 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6substituted purines, comprising 2-aminopropyladenine, 5-propynyluraciland 5-propynylcytosine. 5-methylcytosine substitutions have been shownto increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y.S., Crooke, S. T. and Lebleu, B., eds, ‘Antisense Research andApplications’, CRC Press, Boca Raton, 1993, pp. 276-278) and are aspectsof base substitutions, even more particularly when combined with2′-O-methoxyethyl sugar modifications. Modified nucleobases aredescribed in U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos.4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272;5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540;5,587,469; 5,596,091; 5,614,617; 5,681,941; 5,750,692; 5,763,588;5,830,653; 6,005,096; and US Patent Application Publication2003/0158403.

Thus, the term “modified” refers to a non-natural sugar, phosphate, orbase that is incorporated into a guide RNA, an endonuclease, or both aguide RNA and an endonuclease. It is not necessary for all positions ina given oligonucleotide to be uniformly modified, and in fact more thanone of the aforementioned modifications may be incorporated in a singleoligonucleotide, or even in a single nucleoside within anoligonucleotide.

In some embodiments, the guide RNAs and/or mRNA (or DNA) encoding anendonuclease are chemically linked to one or more moieties or conjugatesthat enhance the activity, cellular distribution, or cellular uptake ofthe oligonucleotide. Such moieties comprise, but are not limited to,lipid moieties such as a cholesterol moiety [Letsinger et al., Proc.Natl. Acad. Sci. USA, 86: 6553-6556 (1989)]; cholic acid [Manoharan etal., Bioorg. Med. Chem. Let., 4: 1053-1060 (1994)]; a thioether, e.g.,hexyl-S-tritylthiol [Manoharan et al, Ann. N. Y. Acad. Sci., 660:306-309 (1992) and Manoharan et al., Bioorg. Med. Chem. Let., 3:2765-2770 (1993)]; a thiocholesterol [Oberhauser et al., Nucl. AcidsRes., 20: 533-538 (1992)]; an aliphatic chain, e.g., dodecandiol orundecyl residues [Kabanov et al., FEBS Lett., 259: 327-330 (1990) andSvinarchuk et al., Biochimie, 75: 49-54 (1993)]; a phospholipid, e.g.,di-hexadecyl-rac-glycerol or triethylammonium1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate [Manoharan et al.,Tetrahedron Lett., 36: 3651-3654 (1995) and Shea et al., Nucl. AcidsRes., 18: 3777-3783 (1990)]; a polyamine or a polyethylene glycol chain[Mancharan et al., Nucleosides & Nucleotides, 14: 969-973 (1995)];adamantane acetic acid [Manoharan et al., Tetrahedron Lett., 36:3651-3654 (1995)]; a palmityl moiety [(Mishra et al., Biochim Biophys.Acta, 1264: 229-237 (1995)]; or an octadecylamine orhexylamino-carbonyl-t oxycholesterol moiety [Crooke et al., J.Pharmacol. Exp. Ther., 277: 923-937 (1996)]. See also U.S. Pat. Nos.4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730;5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124;5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718;5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737;4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830;5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022;5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098;5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667;5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371;5,595,726; 5,597,696; 5,599,923; 5,599, 928 and 5,688,941.

Sugars and other moieties can be used to target proteins and complexescomprising nucleotides, such as cationic polysomes and liposomes, toparticular sites. For example, hepatic cell directed transfer can bemediated via asialoglycoprotein receptors (ASGPRs); see, e.g., Hu, etal., Protein Pept Lett. 21(10):1025-30 (2014). Other systems known inthe art and regularly developed can be used to target biomolecules ofuse in the present case and/or complexes thereof to particular targetcells of interest.

These targeting moieties or conjugates can include conjugate groupscovalently bound to functional groups, such as primary or secondaryhydroxyl groups. Conjugate groups of the disclosure includeintercalators, reporter molecules, polyamines, polyamides, polyethyleneglycols, polyethers, groups that enhance the pharmacodynamic propertiesof oligomers, and groups that enhance the pharmacokinetic properties ofoligomers. Typical conjugate groups include cholesterols, lipids,phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone,acridine, fluoresceins, rhodamines, coumarins, and dyes. Groups thatenhance the pharmacodynamic properties, in the context of thisdisclosure, include groups that improve uptake, enhance resistance todegradation, and/or strengthen sequence-specific hybridization with thetarget nucleic acid. Groups that enhance the pharmacokinetic properties,in the context of this disclosure, include groups that improve uptake,distribution, metabolism or excretion of the compounds of the presentdisclosure. Representative conjugate groups are disclosed inInternational Patent Application No. PCT/US92/09196, filed Oct. 23,1992, and U.S. Pat. No. 6,287,860, which are incorporated herein byreference. Conjugate moieties include, but are not limited to, lipidmoieties such as a cholesterol moiety, cholic acid, a thioether, e.g.,hexyl-5-tritylthiol, a thiocholesterol, an aliphatic chain, e.g.,dodecandiol or undecyl residues, a phospholipid, e.g.,di-hexadecyl-rac-glycerol or triethylammonium1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate, a polyamine or apolyethylene glycol chain, or adamantane acetic acid, a palmityl moiety,or an octadecylamine or hexylamino-carbonyl-oxy cholesterol moiety. See,e.g., U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465;5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731;5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603;5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025;4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582;4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963;5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250;5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463;5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142;5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and5,688,941.

Longer polynucleotides that are less amenable to chemical synthesis andare typically produced by enzymatic synthesis can also be modified byvarious means. Such modifications can include, for example, theintroduction of certain nucleotide analogs, the incorporation ofparticular sequences or other moieties at the 5′ or 3′ ends ofmolecules, and other modifications. By way of illustration, the mRNAencoding Cas9 is approximately 4 kb in length and can be synthesized byin vitro transcription. Modifications to the mRNA can be applied to,e.g., increase its translation or stability (such as by increasing itsresistance to degradation with a cell), or to reduce the tendency of theRNA to elicit an innate immune response that is often observed in cellsfollowing introduction of exogenous RNAs, particularly longer RNAs suchas that encoding Cas9.

Numerous such modifications have been described in the art, such aspolyA tails, 5′ cap analogs (e.g., Anti Reverse Cap Analog (ARCA) orm7G(5′)ppp(5′)G (mCAP)), modified 5′ or 3′ untranslated regions (UTRs),use of modified bases (such as Pseudo-UTP, 2-Thio-UTP,5-Methylcytidine-5′-Triphosphate (5-Methyl-CTP) or N6-Methyl-ATP), ortreatment with phosphatase to remove 5′ terminal phosphates. These andother modifications are known in the art, and new modifications of RNAsare regularly being developed.

There are numerous commercial suppliers of modified RNAs, including forexample, TriLink Biotech, AxoLabs, Bio-Synthesis Inc., Dharmacon andmany others. As described by TriLink, for example, 5-Methyl-CTP can beused to impart desirable characteristics, such as increased nucleasestability, increased translation or reduced interaction of innate immunereceptors with in vitro transcribed RNA.5-Methylcytidine-5′-Triphosphate (5-Methyl-CTP), N6-Methyl-ATP, as wellas Pseudo-UTP and 2-Thio-UTP, have also been shown to reduce innateimmune stimulation in culture and in vivo while enhancing translation,as illustrated in publications by Kormann et al. and Warren et al.referred to below.

It has been shown that chemically modified mRNA delivered in vivo can beused to achieve improved therapeutic effects; see, e.g., Kormann et al.,Nature Biotechnology 29, 154-157 (2011). Such modifications can be used,for example, to increase the stability of the RNA molecule and/or reduceits immunogenicity. Using chemical modifications such as Pseudo-U,N6-Methyl-A, 2-Thio-U and 5-Methyl-C, it was found that substitutingjust one quarter of the uridine and cytidine residues with 2-Thio-U and5-Methyl-C respectively resulted in a significant decrease in toll-likereceptor (TLR) mediated recognition of the mRNA in mice. By reducing theactivation of the innate immune system, these modifications can be usedto effectively increase the stability and longevity of the mRNA in vivo;see, e.g., Kormann et al., supra.

It has also been shown that repeated administration of syntheticmessenger RNAs incorporating modifications designed to bypass innateanti-viral responses can reprogram differentiated human cells topluripotency. See, e.g., Warren, et al., Cell Stem Cell, 7(5):618-30(2010). Such modified mRNAs that act as primary reprogramming proteinscan be an efficient means of reprogramming multiple human cell types.Such cells are referred to as induced pluripotency stem cells (iPSCs),and it was found that enzymatically synthesized RNA incorporating5-Methyl-CTP, Pseudo-UTP and an Anti Reverse Cap Analog (ARCA) could beused to effectively evade the cell's antiviral response; see, e.g.,Warren et al., supra.

Other modifications of polynucleotides described in the art include, forexample, the use of polyA tails, the addition of 5′ cap analogs (such asm7G(5′)ppp(5′)G (mCAP)), modifications of 5′ or 3′ untranslated regions(UTRs), or treatment with phosphatase to remove 5′ terminalphosphates—and new approaches are regularly being developed.

A number of compositions and techniques applicable to the generation ofmodified RNAs for use herein have been developed in connection with themodification of RNA interference (RNAi), including small-interferingRNAs (siRNAs). siRNAs present particular challenges in vivo becausetheir effects on gene silencing via mRNA interference are generallytransient, which can require repeat administration. In addition, siRNAsare double-stranded RNAs (dsRNA) and mammalian cells have immuneresponses that have evolved to detect and neutralize dsRNA, which isoften a by-product of viral infection. Thus, there are mammalian enzymessuch as PKR (dsRNA-responsive kinase), and potentially retinoicacid-inducible gene I (RIG-I), that can mediate cellular responses todsRNA, as well as Toll-like receptors (such as TLR3, TLR7 and TLR8) thatcan trigger the induction of cytokines in response to such molecules;see, e.g., the reviews by Angart et al., Pharmaceuticals (Basel) 6(4):440-468 (2013); Kanasty et al., Molecular Therapy 20(3): 513-524 (2012);Burnett et al., Biotechnol J. 6(9):1130-46 (2011); Judge and MacLachlan,Hum Gene Ther 19(2):111-24 (2008); and references cited therein.

A large variety of modifications have been developed and applied toenhance RNA stability, reduce innate immune responses, and/or achieveother benefits that can be useful in connection with the introduction ofpolynucleotides into human cells, as described herein; see, e.g., thereviews by Whitehead K A et al., Annual Review of Chemical andBiomolecular Engineering, 2: 77-96 (2011); Gaglione and Messere, MiniRev Med Chem, 10(7):578-95 (2010); Chernolovskaya et al, Curr Opin MolTher., 12(2):158-67 (2010); Deleavey et al., Curr Protoc Nucleic AcidChem Chapter 16: Unit 16.3 (2009); Behlke, Oligonucleotides 18(4):305-19(2008); Fucini et al., Nucleic Acid Ther 22(3): 205-210 (2012); Bremsenet al., Front Genet 3:154 (2012).

As noted above, there are a number of commercial suppliers of modifiedRNAs, many of which have specialized in modifications designed toimprove the effectiveness of siRNAs. A variety of approaches are offeredbased on various findings reported in the literature. For example,Dharmacon notes that replacement of a non-bridging oxygen with sulfur(phosphorothioate, PS) has been extensively used to improve nucleaseresistance of siRNAs, as reported by Kole, Nature Reviews Drug Discovery11:125-140 (2012). Modifications of the 2′-position of the ribose havebeen reported to improve nuclease resistance of the internucleotidephosphate bond while increasing duplex stability (Tm), which has alsobeen shown to provide protection from immune activation. A combinationof moderate PS backbone modifications with small, well-tolerated2′-substitutions (2′-O-Methyl, 2′-Fluoro, 2′-Hydro) have been associatedwith highly stable siRNAs for applications in vivo, as reported bySoutschek et al. Nature 432:173-178 (2004); and 2′-O-Methylmodifications have been reported to be effective in improving stabilityas reported by Volkov, Oligonucleotides 19:191-202 (2009). With respectto decreasing the induction of innate immune responses, modifyingspecific sequences with 2′-O-Methyl, 2′-Fluoro, 2′-Hydro have beenreported to reduce TLR7/TLR8 interaction while generally preservingsilencing activity; see, e.g., Judge et al., Mol. Ther. 13:494-505(2006); and Cekaite et al., J. Mol. Biol. 365:90-108 (2007). Additionalmodifications, such as 2-thiouracil, pseudouracil, 5-methylcytosine,5-methyluracil, and N6-methyladenosine have also been shown to minimizethe immune effects mediated by TLR3, TLR7, and TLR8; see, e.g., Kariko,K. et al., Immunity 23:165-175 (2005).

As is also known in the art, and commercially available, a number ofconjugates can be applied to polynucleotides, such as RNAs, for useherein that can enhance their delivery and/or uptake by cells, includingfor example, cholesterol, tocopherol and folic acid, lipids, peptides,polymers, linkers and aptamers; see, e.g., the review by Winkler, Ther.Deliv. 4:791-809 (2013), and references cited therein.

Codon-Optimization

In some embodiments, a polynucleotide encoding a site-directedpolypeptide is codon-optimized according to methods standard in the artfor expression in the cell containing the target DNA of interest. Forexample, if the intended target nucleic acid is in a human cell, a humancodon-optimized polynucleotide encoding Cas9 is contemplated for use forproducing the Cas9 polypeptide.

Complexes of a Genome-Targeting Nucleic Acid and a Site-DirectedPolypeptide

A genome-targeting nucleic acid interacts with a site-directedpolypeptide (e.g., a nucleic acid-guided nuclease such as Cas9), therebyforming a complex. The genome-targeting nucleic acid guides thesite-directed polypeptide to a target nucleic acid.

RNPs

The site-directed polypeptide and genome-targeting nucleic acid may eachbe administered separately to a cell or a patient. On the other hand,the site-directed polypeptide may be pre-complexed with one or moreguide RNAs, or one or more crRNA together with a tracrRNA. Thepre-complexed material may then be administered to a cell or a patient.Such pre-complexed material is known as a ribonucleoprotein particle(RNP).

Nucleic Acids Encoding System Components

The present disclosure provides a nucleic acid comprising a nucleotidesequence encoding a genome-targeting nucleic acid of the disclosure, asite-directed polypeptide of the disclosure, and/or any nucleic acid orproteinaceous molecule necessary to carry out the aspects of the methodsof the disclosure.

The nucleic acid encoding a genome-targeting nucleic acid of thedisclosure, a site-directed polypeptide of the disclosure, and/or anynucleic acid or proteinaceous molecule necessary to carry out theaspects of the methods of the disclosure comprises a vector (e.g., arecombinant expression vector).

The term “vector” refers to a nucleic acid molecule capable oftransporting another nucleic acid to which it has been linked. One typeof vector is a “plasmid”, which refers to a circular double-stranded DNAloop into which additional nucleic acid segments can be ligated. Anothertype of vector is a viral vector (e.g., AAV), wherein additional nucleicacid segments can be ligated into the viral genome. Certain vectors arecapable of autonomous replication in a host cell into which they areintroduced (e.g., bacterial vectors having a bacterial origin ofreplication and episomal mammalian vectors). Other vectors (e.g.,non-episomal mammalian vectors) are integrated into the genome of a hostcell upon introduction into the host cell, and thereby are replicatedalong with the host genome.

In some embodiments, vectors are capable of directing the expression ofnucleic acids to which they are operatively linked. Such vectors arereferred to herein as “recombinant expression vectors”, or more simply“expression vectors”, which serve equivalent functions.

The term “operably linked” means that the nucleotide sequence ofinterest is linked to regulatory sequence(s) in a manner that allows forexpression of the nucleotide sequence. The term “regulatory sequence” isintended to include, for example, promoters, enhancers and otherexpression control elements (e.g., polyadenylation signals). Suchregulatory sequences are well known in the art and are described, forexample, in Goeddel; Gene Expression Technology: Methods in Enzymology185, Academic Press, San Diego, Calif. (1990). Regulatory sequencesinclude those that direct constitutive expression of a nucleotidesequence in many types of host cells, and those that direct expressionof the nucleotide sequence only in certain host cells (e.g.,tissue-specific regulatory sequences). It will be appreciated by thoseskilled in the art that the design of the expression vector can dependon such factors as the choice of the target cell, the level ofexpression desired, and the like.

Expression vectors contemplated include, but are not limited to, viralvectors based on vaccinia virus, poliovirus, adenovirus,adeno-associated virus, SV40, herpes simplex virus, humanimmunodeficiency virus, retrovirus (e.g., Murine Leukemia Virus, spleennecrosis virus, and vectors derived from retroviruses such as RousSarcoma Virus, Harvey Sarcoma Virus, avian leukosis virus, a lentivirus,human immunodeficiency virus, myeloproliferative sarcoma virus, andmammary tumor virus) and other recombinant vectors. Other vectorscontemplated for eukaryotic target cells include, but are not limitedto, the vectors pXT1, pSG5, pSVK3, pBPV, pMSG, and pSVLSV40 (Pharmacia).Additional vectors contemplated for eukaryotic target cells include, butare not limited to, the vectors. Other vectors may be used so long asthey are compatible with the host cell.

In some embodiments, a vector comprises one or more transcription and/ortranslation control elements. Depending on the host/vector systemutilized, any of a number of suitable transcription and translationcontrol elements, including constitutive and inducible promoters,transcription enhancer elements, transcription terminators, etc. may beused in the expression vector. In some embodiments, the vector is aself-inactivating vector that either inactivates the viral sequences orthe components of the CRISPR machinery or other elements.

Non-limiting examples of suitable eukaryotic promoters (i.e., promotersfunctional in a eukaryotic cell) include those from cytomegalovirus(CMV) immediate early, herpes simplex virus (HSV) thymidine kinase,early and late SV40, long terminal repeats (LTRs) from retrovirus, humanelongation factor-1 promoter (EF1), a hybrid construct comprising thecytomegalovirus (CMV) enhancer fused to the chicken beta-actin promoter(CAG), murine stem cell virus promoter (MSCV), phosphoglycerate kinase-1locus promoter (PGK), and mouse metallothionein-I.

For expressing small RNAs, including guide RNAs used in connection withCas endonuclease, various promoters such as RNA polymerase IIIpromoters, including for example U6 and H1, can be advantageous.Descriptions of and parameters for enhancing the use of such promotersare known in art, and additional information and approaches areregularly being described; see, e.g., Ma, H. et al., MolecularTherapy—Nucleic Acids 3, e161 (2014) doi:10.1038/mtna.2014.12.

The expression vector may also contain a ribosome binding site fortranslation initiation and a transcription terminator. The expressionvector may also comprise appropriate sequences for amplifyingexpression. The expression vector may also include nucleotide sequencesencoding non-native tags (e.g., histidine tag, hemagglutinin tag, greenfluorescent protein, etc.) that are fused to the site-directedpolypeptide, thus resulting in a fusion protein.

In some embodiments, a promoter is an inducible promoter (e.g., a heatshock promoter, tetracycline-regulated promoter, steroid-regulatedpromoter, metal-regulated promoter, estrogen receptor-regulatedpromoter, etc.). In some embodiments, the promoter is a constitutivepromoter (e.g., CMV promoter, UBC promoter). In some embodiments, thepromoter is a spatially restricted and/or temporally restricted promoter(e.g., a tissue specific promoter, a cell type specific promoter, etc.).

In some embodiments, the nucleic acid encoding a genome-targetingnucleic acid of the disclosure and/or a site-directed polypeptide ispackaged into or on the surface of delivery vehicles for delivery tocells. Delivery vehicles contemplated include, but are not limited to,nanospheres, liposomes, quantum dots, nanoparticles, polyethylene glycolparticles, hydrogels, and micelles. As described in the art, a varietyof targeting moieties can be used to enhance the preferentialinteraction of such vehicles with desired cell types or locations.

Introduction of the complexes, polypeptides, and nucleic acids of thedisclosure into cells can occur by viral or bacteriophage infection,transfection, conjugation, protoplast fusion, lipofection,electroporation, nucleofection, calcium phosphate precipitation,polyethyleneimine (PEI)-mediated transfection, DEAE-dextran mediatedtransfection, liposome-mediated transfection, particle gun technology,calcium phosphate precipitation, direct micro-injection,nanoparticle-mediated nucleic acid delivery, and the like.

Delivery

Guide RNA polynucleotides (RNA or DNA) and/or endonucleasepolynucleotide(s) (RNA or DNA) can be delivered by viral or non-viraldelivery vehicles known in the art. Alternatively, endonucleasepolypeptide(s) may be delivered by viral or non-viral delivery vehiclesknown in the art, such as electroporation or lipid nanoparticles. Insome embodiments, the DNA endonuclease may be delivered as one or morepolypeptides, either alone or pre-complexed with one or more guide RNAs,or one or more crRNA together with a tracrRNA.

Polynucleotides may be delivered by non-viral delivery vehiclesincluding, but not limited to, nanoparticles, liposomes,ribonucleoproteins, positively charged peptides, small moleculeRNA-conjugates, aptamer-RNA chimeras, and RNA-fusion protein complexes.Some exemplary non-viral delivery vehicles are described in Peer andLieberman, Gene Therapy, 18: 1127-1133 (2011) (which focuses onnon-viral delivery vehicles for siRNA that are also useful for deliveryof other polynucleotides).

Polynucleotides, such as guide RNA, sgRNA, and mRNA encoding anendonuclease, may be delivered to a cell or a patient by a lipidnanoparticle (LNP).

A LNP refers to any particle having a diameter of less than 1000 nm, 500nm, 250 nm, 200 nm, 150 nm, 100 nm, 75 nm, 50 nm, or 25 nm.Alternatively, a nanoparticle may range in size from 1-1000 nm, 1-500nm, 1-250 nm, 25-200 nm, 25-100 nm, 35-75 nm, or 25-60 nm.

LNPs may be made from cationic, anionic, or neutral lipids. Neutrallipids, such as the fusogenic phospholipid DOPE or the membranecomponent cholesterol, may be included in LNPs as ‘helper lipids’ toenhance transfection activity and nanoparticle stability. Limitations ofcationic lipids include low efficacy owing to poor stability and rapidclearance, as well as the generation of inflammatory oranti-inflammatory responses.

LNPs may also be comprised of hydrophobic lipids, hydrophilic lipids, orboth hydrophobic and hydrophilic lipids.

Any lipid or combination of lipids that are known in the art may be usedto produce a LNP. Examples of lipids used to produce LNPs are: DOTMA,DOSPA, DOTAP, DMRIE, DC-cholesterol, DOTAP-cholesterol,GAP-DMORIE-DPyPE, and GL67A-DOPE-DMPE-polyethylene glycol (PEG).Examples of cationic lipids are: 98N12-5, C12-200, DLin-KC2-DMA (KC2),DLin-MC3-DMA (MC3), XTC, MD1, and 7C1. Examples of neutral lipids are:DPSC, DPPC, POPC, DOPE, and SM. Examples of PEG-modified lipids are: PEGPEG-CerC14, and PEG-CerC20.

The lipids may be combined in any number of molar ratios to produce aLNP. In addition, the polynucleotide(s) may be combined with lipid(s) ina wide range of molar ratios to produce a LNP.

As stated previously, the site-directed polypeptide and genome-targetingnucleic acid may each be administered separately to a cell or a patient.On the other hand, the site-directed polypeptide may be pre-complexedwith one or more guide RNAs, or one or more crRNA together with atracrRNA. The pre-complexed material may then be administered to a cellor a patient. Such pre-complexed material is known as aribonucleoprotein particle (RNP).

RNA is capable of forming specific interactions with RNA or DNA. Whilethis property is exploited in many biological processes, it also comeswith the risk of promiscuous interactions in a nucleic acid-richcellular environment. One solution to this problem is the formation ofribonucleoprotein particles (RNPs), in which the RNA is pre-complexedwith an endonuclease. Another benefit of the RNP is protection of theRNA from degradation.

The endonuclease in the RNP may be modified or unmodified. Likewise, thegRNA, crRNA, tracrRNA, or sgRNA may be modified or unmodified. Numerousmodifications are known in the art and may be used.

The endonuclease and sgRNA may be generally combined in a 1:1 molarratio. Alternatively, the endonuclease, crRNA and tracrRNA may begenerally combined in a 1:1:1 molar ratio. However, a wide range ofmolar ratios may be used to produce a RNP.

A recombinant adeno-associated virus (AAV) vector may be used fordelivery. Techniques to produce rAAV particles, in which an AAV genometo be packaged that includes the polynucleotide to be delivered, rep andcap genes, and helper virus functions are provided to a cell arestandard in the art. Production of rAAV requires that the followingcomponents are present within a single cell (denoted herein as apackaging cell): a rAAV genome, AAV rep and cap genes separate from(i.e., not in) the rAAV genome, and helper virus functions. The AAV repand cap genes may be from any AAV serotype for which recombinant viruscan be derived, and may be from a different AAV serotype than the rAAVgenome ITRs, including, but not limited to, AAV serotypes AAV-1, AAV-2,AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, AAV-11, AAV-12,AAV-13 and AAV rh.74. Production of pseudotyped rAAV is disclosed in,for example, international patent application publication number WO01/83692. See Table 2.

TABLE 2 AAV Serotype Genbank Accession No. AAV-1 NC_002077.1 AAV-2NC_001401.2 AAV-3 NC_001729.1 AAV-3B AF028705.1 AAV-4 NC_001829.1 AAV-5NC_006152.1 AAV-6 AF028704.1 AAV-7 NC_006260.1 AAV-8 NC_006261.1 AAV-9AX753250.1 AAV-10 AY631965.1 AAV-11 AY631966.1 AAV-12 DQ813647.1 AAV-13EU285562.1

A method of generating a packaging cell involves creating a cell linethat stably expresses all of the necessary components for AAV particleproduction. For example, a plasmid (or multiple plasmids) comprising arAAV genome lacking AAV rep and cap genes, AAV rep and cap genesseparate from the rAAV genome, and a selectable marker, such as aneomycin resistance gene, are integrated into the genome of a cell. AAVgenomes have been introduced into bacterial plasmids by procedures suchas GC tailing (Samulski et al., 1982, Proc. Natl. Acad. S6. USA,79:2077-2081), addition of synthetic linkers containing restrictionendonuclease cleavage sites (Laughlin et al., 1983, Gene, 23:65-73) orby direct, blunt-end ligation (Senapathy & Carter, 1984, J. Biol. Chem.,259:4661-4666). The packaging cell line is then infected with a helpervirus, such as adenovirus. The advantages of this method are that thecells are selectable and are suitable for large-scale production ofrAAV. Other examples of suitable methods employ adenovirus orbaculovirus, rather than plasmids, to introduce rAAV genomes and/or repand cap genes into packaging cells.

General principles of rAAV production are reviewed in, for example,Carter, 1992, Current Opinions in Biotechnology, 1533-539; and Muzyczka,1992, Curr. Topics in Microbial. and Immunol., 158:97-129). Variousapproaches are described in Ratschin et al., Mol. Cell. Biol. 4:2072(1984); Hermonat et al., Proc. Natl. Acad. Sci. USA, 81:6466 (1984);Tratschin et al., Mol. Cell. Biol. 5:3251 (1985); McLaughlin et al., J.Virol., 62:1963 (1988); and Lebkowski et al., 1988 Mol. Cell. Biol.,7:349 (1988). Samulski et al. (1989, J. Virol., 63:3822-3828); U.S. Pat.No. 5,173,414; WO 95/13365 and corresponding U.S. Pat. No. 5,658,776; WO95/13392; WO 96/17947; PCT/US98/18600; WO 97/09441 (PCT/US96/14423); WO97/08298 (PCT/US96/13872); WO 97/21825 (PCT/US96/20777); WO 97/06243(PCT/FR96/01064); WO 99/11764; Perrin et al. (1995) Vaccine13:1244-1250; Paul et al. (1993) Human Gene Therapy 4:609-615; Clark etal. (1996) Gene Therapy 3:1124-1132; U.S. Pat. Nos. 5,786,211;5,871,982; and 6,258,595.

AAV vector serotypes can be matched to target cell types. For example,the following exemplary cell types may be transduced by the indicatedAAV serotypes among others. See Table 3.

TABLE 3 Tissue/Cell Type Serotype Liver AAV3, AAV5, AAV8, AAV9 Skeletalmuscle AAV1, AAV7, AAV6, AAV8, AAV9 Central nervous system AAV5, AAV1,AAV4 RPE AAV5, AAV4 Photoreceptor cells AAV5 Lung AAV9 Heart AAV8Pancreas AAV8 Kidney AAV2, AAV8 Hematopoietic stem cells AAV6

In addition to adeno-associated viral vectors, other viral vectors canbe used. Such viral vectors include, but are not limited to, lentivirus,alphavirus, enterovirus, pestivirus, baculovirus, herpesvirus, EpsteinBarr virus, papovavirusr, poxvirus, vaccinia virus, and herpes simplexvirus.

In some embodiments, Cas9 mRNA, sgRNA targeting one or two loci intarget gene, and donor DNA is each separately formulated into lipidnanoparticles, or are all co-formulated into one lipid nanoparticle, orco-formulated into two or more lipid nanoparticles.

In some embodiments, Cas9 mRNA is formulated in a lipid nanoparticle,while sgRNA and donor DNA are delivered in an AAV vector. In someembodiments, Cas9 mRNA and sgRNA are co-formulated in a lipidnanoparticle, while donor DNA is delivered in an AAV vector.

Options are available to deliver the Cas9 nuclease as a DNA plasmid, asmRNA or as a protein. The guide RNA can be expressed from the same DNA,or can also be delivered as an RNA. The RNA can be chemically modifiedto alter or improve its half-life, or decrease the likelihood or degreeof immune response. The endonuclease protein can be complexed with thegRNA prior to delivery. Viral vectors allow efficient delivery; splitversions of Cas9 and smaller orthologs of Cas9 can be packaged in AAV,as can donors for HDR. A range of non-viral delivery methods also existthat can deliver each of these components, or non-viral and viralmethods can be employed in tandem. For example, nano-particles can beused to deliver the protein and guide RNA, while AAV can be used todeliver a donor DNA.

Exosomes

Exosomes, a type of microvesicle bound by phospholipid bilayer, can beused to deliver nucleic acids to specific tissue. Many different typesof cells within the body naturally secrete exosomes. Exosomes formwithin the cytoplasm when endosomes invaginate and formmultivesicular-endosomes (MVE). When the MVE fuses with the cellularmembrane, the exosomes are secreted in the extracellular space. Rangingbetween 30-120 nm in diameter, exosomes can shuttle various moleculesfrom one cell to another in a form of cell-to-cell communication. Cellsthat naturally produce exosomes, such as mast cells, can be geneticallyaltered to produce exosomes with surface proteins that target specifictissues, alternatively exosomes can be isolated from the bloodstream.Specific nucleic acids can be placed within the engineered exosomes withelectroporation. When introduced systemically, the exosomes can deliverthe nucleic acids to the specific target tissue.

Genetically Modified Cells

The term “genetically modified cell” refers to a cell that comprises atleast one genetic modification introduced by genome editing (e.g., usingthe CRISPR/Cas9/Cpf1 system). In some examples, (e.g., ex vivo examples)herein, the genetically modified cell is genetically modified progenitorcell. In some examples herein, the genetically modified cell isgenetically modified T cell. A genetically modified cell comprising anexogenous genome-targeting nucleic acid and/or an exogenous nucleic acidencoding a genome-targeting nucleic acid is contemplated herein.

The term “control treated population” describes a population of cellsthat has been treated with identical media, viral induction, nucleicacid sequences, temperature, confluency, flask size, pH, etc., with theexception of the addition of the genome editing components. Any methodknown in the art can be used to measure restoration of target gene orprotein expression or activity, for example Western Blot analysis of thetarget protein or quantifying target mRNA.

The term “isolated cell” refers to a cell that has been removed from anorganism in which it was originally found, or a descendant of such acell. Optionally, the cell is cultured in vitro, e.g., under definedconditions or in the presence of other cells. Optionally, the cell islater introduced into a second organism or re-introduced into theorganism from which it (or the cell from which it is descended) wasisolated.

The term “isolated population” with respect to an isolated population ofcells refers to a population of cells that has been removed andseparated from a mixed or heterogeneous population of cells. In someembodiments, the isolated population is a substantially pure populationof cells, as compared to the heterogeneous population from which thecells were isolated or enriched. In some embodiments, the isolatedpopulation is an isolated population of human progenitor cells, e.g., asubstantially pure population of human progenitor cells, as compared toa heterogeneous population of cells comprising human progenitor cellsand cells from which the human progenitor cells were derived.

The term “substantially enhanced,” with respect to a particular cellpopulation, refers to a population of cells in which the occurrence of aparticular type of cell is increased relative to pre-existing orreference levels, by at least 2-fold, at least 3-, at least 4-, at least5-, at least 6-, at least 7-, at least 8-, at least 9, at least 10-, atleast 20-, at least 50-, at least 100-, at least 400-, at least 1000-,at least 5000-, at least 20000-, at least 100000- or more folddepending, e.g., on the desired levels of such cells for ameliorating amedical condition.

The term “substantially enriched” with respect to a particular cellpopulation, refers to a population of cells that is at least about 10%,about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or morewith respect to the cells making up a total cell population.

The terms “substantially enriched” or “substantially pure” with respectto a particular cell population, refers to a population of cells that isat least about 75%, at least about 85%, at least about 90%, or at leastabout 95% pure, with respect to the cells making up a total cellpopulation. That is, the terms “substantially pure” or “essentiallypurified,” with regard to a population of progenitor cells, refers to apopulation of cells that contain fewer than about 20%, about 15%, about10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about3%, about 2%, about 1%, or less than 1%, of cells that are notprogenitor cells as defined by the terms herein.

Implanting Cells into Patients

Another step of the ex vivo methods of the present disclosure comprisesimplanting the cells into patients. This implanting step may beaccomplished using any method of implantation known in the art. Forexample, the genetically modified cells may be injected directly in thepatient's blood or otherwise administered to the patient. Thegenetically modified cells may be purified ex vivo using a selectedmarker.

Pharmaceutically Acceptable Carriers

The ex vivo methods of administering progenitor cells to a subjectcontemplated herein involve the use of therapeutic compositionscomprising progenitor cells.

Therapeutic compositions contain a physiologically tolerable carriertogether with the cell composition, and optionally at least oneadditional bioactive agent as described herein, dissolved or dispersedtherein as an active ingredient. In some embodiments, the therapeuticcomposition is not substantially immunogenic when administered to amammal or human patient for therapeutic purposes, unless so desired.

In general, the progenitor cells described herein are administered as asuspension with a pharmaceutically acceptable carrier. One of skill inthe art will recognize that a pharmaceutically acceptable carrier to beused in a cell composition will not include buffers, compounds,cryopreservation agents, preservatives, or other agents in amounts thatsubstantially interfere with the viability of the cells to be deliveredto the subject. A formulation comprising cells can include e.g., osmoticbuffers that permit cell membrane integrity to be maintained, andoptionally, nutrients to maintain cell viability or enhance engraftmentupon administration. Such formulations and suspensions are known tothose of skill in the art and/or can be adapted for use with theprogenitor cells, as described herein, using routine experimentation.

A cell composition can also be emulsified or presented as a liposomecomposition, provided that the emulsification procedure does notadversely affect cell viability. The cells and any other activeingredient can be mixed with excipients that are pharmaceuticallyacceptable and compatible with the active ingredient, and in amountssuitable for use in the therapeutic methods described herein.

Additional agents included in a cell composition can includepharmaceutically acceptable salts of the components therein.Pharmaceutically acceptable salts include the acid addition salts(formed with the free amino groups of the polypeptide) that are formedwith inorganic acids, such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, tartaric, mandelic and the like.Salts formed with the free carboxyl groups can also be derived frominorganic bases, such as, for example, sodium, potassium, ammonium,calcium or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.

Physiologically tolerable carriers are well known in the art. Exemplaryliquid carriers are sterile aqueous solutions that contain no materialsin addition to the active ingredients and water, or contain a buffersuch as sodium phosphate at physiological pH value, physiological salineor both, such as phosphate-buffered saline. Still further, aqueouscarriers can contain more than one buffer salt, as well as salts such assodium and potassium chlorides, dextrose, polyethylene glycol and othersolutes. Liquid compositions can also contain liquid phases in additionto and to the exclusion of water. Exemplary of such additional liquidphases are glycerin, vegetable oils such as cottonseed oil, andwater-oil emulsions. The amount of an active compound used in the cellcompositions that is effective in the treatment of a particular disorderor condition will depend on the nature of the disorder or condition, andcan be determined by standard clinical techniques.

Administration & Efficacy

The terms “administering,” “introducing” and “transplanting” are usedinterchangeably in the context of the placement of cells, e.g.,progenitor cells, into a subject, by a method or route that results inat least partial localization of the introduced cells at a desired site,such as a site of injury or repair, such that a desired effect(s) isproduced. The cells e.g., progenitor cells, or their differentiatedprogeny can be administered by any appropriate route that results indelivery to a desired location in the subject where at least a portionof the implanted cells or components of the cells remain viable. Theperiod of viability of the cells after administration to a subject canbe as short as a few hours, e.g., twenty-four hours, to a few days, toas long as several years, or even the life time of the patient, i.e.,long-term engraftment. For example, in some aspects described herein, aneffective amount of myogenic progenitor cells is administered via asystemic route of administration, such as an intraperitoneal orintravenous route.

The terms “individual”, “subject,” “host” and “patient” are usedinterchangeably herein and refer to any subject for whom diagnosis,treatment or therapy is desired. In some aspects, the subject is amammal. In some aspects, the subject is a human being.

The term “donor” is used to refer to an individual that is not thepatient. In some embodiments, the donor is an individual who does nothave or is not suspected of having the medical condition to be treated.In some embodiments, multiple donors, e.g., two or more donors, can beused. In some embodiments, each donor used is an individual who does nothave or is not suspected of having the medical condition to be treated.

When provided prophylactically, progenitor cells described herein can beadministered to a subject in advance of any symptom of a medicalcondition, e.g., prior to the development of alpha/beta T-celllymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus(CMV) infection, autoimmunity, chronic inflammation of the skin,eosinophilia, failure to thrive, swollen lymph nodes, swollen spleen,diarrhea and enlarged liver. Accordingly, the prophylacticadministration of a hematopoietic progenitor cell population serves toprevent a medical condition.

When provided therapeutically, hematopoietic progenitor cells areprovided at (or after) the onset of a symptom or indication of a medicalcondition, e.g., upon the onset of disease.

In some embodiments, the T cell population being administered accordingto the methods described herein comprises allogeneic T cells obtainedfrom one or more donors. In some embodiments, the cell population beingadministered can be allogeneic blood cells, hematopoietic stem cells,hematopoietic progenitor cells, embryonic stem cells, or inducedembryonic stem cells. “Allogeneic” refers to a cell, cell population, orbiological samples comprising cells, obtained from one or more differentdonors of the same species, where the genes at one or more loci are notidentical to the recipient. For example, a hematopoietic progenitor cellpopulation, or T cell population, being administered to a subject can bederived from one or more unrelated donors, or from one or morenon-identical siblings. In some embodiments, syngeneic cell populationsmay be used, such as those obtained from genetically identical donors,(e.g., identical twins). In some embodiments, the cells are autologouscells; that is, the cells (e.g.: hematopoietic progenitor cells, or Tcells) are obtained or isolated from a subject and administered to thesame subject, i.e., the donor and recipient are the same.

The term “effective amount” refers to the amount of a population ofprogenitor cells or their progeny needed to prevent or alleviate atleast one or more signs or symptoms of a medical condition, and relatesto a sufficient amount of a composition to provide the desired effect,e.g., to treat a subject having a medical condition. The term“therapeutically effective amount” therefore refers to an amount ofprogenitor cells or a composition comprising progenitor cells that issufficient to promote a particular effect when administered to a typicalsubject, such as one who has or is at risk for a medical condition. Aneffective amount would also include an amount sufficient to prevent ordelay the development of a symptom of the disease, alter the course of asymptom of the disease (for example but not limited to, slow theprogression of a symptom of the disease), or reverse a symptom of thedisease. It is understood that for any given case, an appropriate“effective amount” can be determined by one of ordinary skill in the artusing routine experimentation.

For use in the various aspects described herein, an effective amount ofprogenitor cells comprises at least 10² progenitor cells, at least 5×10²progenitor cells, at least 10³ progenitor cells, at least 5×10³progenitor cells, at least 10⁴ progenitor cells, at least 5×10⁴progenitor cells, at least 10⁵ progenitor cells, at least 2×10⁵progenitor cells, at least 3×10⁵ progenitor cells, at least 4×10⁵progenitor cells, at least 5×10⁵ progenitor cells, at least 6×10⁵progenitor cells, at least 7×10⁵ progenitor cells, at least 8×10⁵progenitor cells, at least 9×10⁵ progenitor cells, at least 1×10⁶progenitor cells, at least 2×10⁶ progenitor cells, at least 3×10⁶progenitor cells, at least 4×10⁶ progenitor cells, at least 5×10⁶progenitor cells, at least 6×10⁶ progenitor cells, at least 7×10⁶progenitor cells, at least 8×10⁶ progenitor cells, at least 9×10⁶progenitor cells, or multiples thereof. The progenitor cells are derivedfrom one or more donors, or are obtained from an autologous source. Insome examples described herein, the progenitor cells are expanded inculture prior to administration to a subject in need thereof.

Modest and incremental increases in the levels of functional targetexpressed in cells of patients having a medical condition can bebeneficial for ameliorating one or more symptoms of the disease, forincreasing long-term survival, and/or for reducing side effectsassociated with other treatments. Upon administration of such cells tohuman patients, the presence of hematopoietic progenitors that areproducing increased levels of functional target is beneficial. In someembodiments, effective treatment of a subject gives rise to at leastabout 3%, 5% or 7% functional target relative to total target in thetreated subject. In some embodiments, functional target will be at leastabout 10% of total target. In some embodiments, functional target willbe at least about 20% to 30% of total target. Similarly, theintroduction of even relatively limited subpopulations of cells havingsignificantly elevated levels of functional target can be beneficial invarious patients because in some situations normalized cells will have aselective advantage relative to diseased cells. However, even modestlevels of hematopoietic progenitors with elevated levels of functionaltarget can be beneficial for ameliorating one or more aspects of amedical condition in patients. In some embodiments, about 10%, about20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%,about 90% or more of the hematopoietic progenitors in patients to whomsuch cells are administered are producing increased levels of functionaltarget.

“Administered” refers to the delivery of a progenitor cell compositioninto a subject by a method or route that results in at least partiallocalization of the cell composition at a desired site. A cellcomposition can be administered by any appropriate route that results ineffective treatment in the subject, i.e. administration results indelivery to a desired location in the subject where at least a portionof the composition delivered, i.e. at least 1×10⁴ cells are delivered tothe desired site for a period of time. Modes of administration includeinjection, infusion, instillation, or ingestion. “Injection” includes,without limitation, intravenous, intramuscular, intra-arterial,intrathecal, intraventricular, intracapsular, intraorbital,intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous,subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal,intracerebro spinal, and intrasternal injection and infusion. In someembodiments, the route is intravenous. For the delivery of cells,administration by injection or infusion can be made.

The cells are administered systemically. The phrases “systemicadministration,” “administered systemically”, “peripheraladministration” and “administered peripherally” refer to theadministration of a population of progenitor cells other than directlyinto a target site, tissue, or organ, such that it enters, instead, thesubject's circulatory system and, thus, is subject to metabolism andother like processes.

The efficacy of a treatment comprising a composition for the treatmentof a medical condition can be determined by the skilled clinician.However, a treatment is considered “effective treatment,” if any one orall of the signs or symptoms of, as but one example, levels offunctional target are altered in a beneficial manner (e.g., increased byat least 10%), or other clinically accepted symptoms or markers ofdisease are improved or ameliorated. Efficacy can also be measured byfailure of an individual to worsen as assessed by hospitalization orneed for medical interventions (e.g., progression of the disease ishalted or at least slowed). Methods of measuring these indicators areknown to those of skill in the art and/or described herein. Treatmentincludes any treatment of a disease in an individual or an animal (somenon-limiting examples include a human, or a mammal) and includes: (1)inhibiting the disease, e.g., arresting, or slowing the progression ofsymptoms; or (2) relieving the disease, e.g., causing regression ofsymptoms; and (3) preventing or reducing the likelihood of thedevelopment of symptoms.

The treatment according to the present disclosure ameliorates one ormore symptoms associated with a medical condition by increasing theamount of functional target in the individual. Early signs typicallyassociated with a medical condition include for example, development ofalpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severecytomegalovirus (CMV) infection, autoimmunity, chronic inflammation ofthe skin, eosinophilia, failure to thrive, swollen lymph nodes, swollenspleen, diarrhea and enlarged liver.

Kits

The present disclosure provides kits for carrying out the methodsdescribed herein. A kit can include one or more of a genome-targetingnucleic acid, a polynucleotide encoding a genome-targeting nucleic acid,a site-directed polypeptide, a polynucleotide encoding a site-directedpolypeptide, and/or any nucleic acid or proteinaceous molecule necessaryto carry out the aspects of the methods described herein, or anycombination thereof.

In some embodiments, a kit comprises: (1) a vector comprising anucleotide sequence encoding a genome-targeting nucleic acid, (2) thesite-directed polypeptide or a vector comprising a nucleotide sequenceencoding the site-directed polypeptide, and (3) a reagent forreconstitution and/or dilution of the vector(s) and or polypeptide.

In some embodiments, a kit comprises: (1) a vector comprising (i) anucleotide sequence encoding a genome-targeting nucleic acid, and (ii) anucleotide sequence encoding the site-directed polypeptide; and (2) areagent for reconstitution and/or dilution of the vector.

In some embodiments of any of the above kits, the kit comprises asingle-molecule guide genome-targeting nucleic acid. In some embodimentsof any of the above kits, the kit comprises a double-moleculegenome-targeting nucleic acid. In some embodiments of any of the abovekits, the kit comprises two or more double-molecule guides orsingle-molecule guides. In some embodiments, the kits comprise a vectorthat encodes the nucleic acid targeting nucleic acid.

In any of the above kits, the kit further comprises a polynucleotide tobe inserted to affect the desired genetic modification.

Components of a kit may be in separate containers, or combined in asingle container.

Any kit described above can further comprise one or more additionalreagents, where such additional reagents are selected from a buffer, abuffer for introducing a polypeptide or polynucleotide into a cell, awash buffer, a control reagent, a control vector, a control RNApolynucleotide, a reagent for in vitro production of the polypeptidefrom DNA, adaptors for sequencing and the like. A buffer can be astabilization buffer, a reconstituting buffer, a diluting buffer, or thelike. In some embodiments, a kit also comprises one or more componentsthat can be used to facilitate or enhance the on-target binding or thecleavage of DNA by the endonuclease, or improve the specificity oftargeting.

In addition to the above-mentioned components, a kit further comprisesinstructions for using the components of the kit to practice themethods. The instructions for practicing the methods are generallyrecorded on a suitable recording medium. For example, the instructionsmay be printed on a substrate, such as paper or plastic, etc. Theinstructions nay be present in the kits as a package insert, in thelabeling of the container of the kit or components thereof (i.e.,associated with the packaging or subpackaging), etc. The instructionscan be present as an electronic storage data file present on a suitablecomputer readable storage medium, e.g. CD-ROM, diskette, flash drive,etc. In some instances, the actual instructions are not present in thekit, but means for obtaining the instructions from a remote source (e.g.via the Internet), can be provided. An example of this case is a kitthat comprises a web address where the instructions can be viewed and/orfrom which the instructions can be downloaded. As with the instructions,this means for obtaining the instructions can be recorded on a suitablesubstrate.

Guide RNA Formulation

Guide RNAs of the present disclosure are formulated withpharmaceutically acceptable excipients such as carriers, solvents,stabilizers, adjuvants, diluents, etc., depending upon the particularmode of administration and dosage form. Guide RNA compositions aregenerally formulated to achieve a physiologically compatible pH, andrange from a pH of about 3 to a pH of about 11, about pH 3 to about pH7, depending on the formulation and route of administration. In someembodiments, the pH is adjusted to a range from about pH 5.0 to about pH8. In some embodiments, the compositions comprise a therapeuticallyeffective amount of at least one compound as described herein, togetherwith one or more pharmaceutically acceptable excipients. Optionally, thecompositions comprise a combination of the compounds described herein,or may include a second active ingredient useful in the treatment orprevention of bacterial growth (for example and without limitation,anti-bacterial or anti-microbial agents), or may include a combinationof reagents of the present disclosure.

Suitable excipients include, for example, carrier molecules that includelarge, slowly metabolized macromolecules such as proteins,polysaccharides, polylactic acids, polyglycolic acids, polymeric aminoacids, amino acid copolymers, and inactive virus particles. Otherexemplary excipients can include antioxidants (for example and withoutlimitation, ascorbic acid), chelating agents (for example and withoutlimitation, EDTA), carbohydrates (for example and without limitation,dextrin, hydroxyalkylcellulose, and hydroxyalkylmethylcellulose),stearic acid, liquids (for example and without limitation, oils, water,saline, glycerol and ethanol), wetting or emulsifying agents, pHbuffering substances, and the like.

Other Possible Therapeutic Approaches

Gene editing can be conducted using nucleases engineered to targetspecific sequences. To date there are four major types of nucleases:meganucleases and their derivatives, zinc finger nucleases (ZFNs),transcription activator like effector nucleases (TALENs), andCRISPR-Cas9 nuclease systems. The nuclease platforms vary in difficultyof design, targeting density and mode of action, particularly as thespecificity of ZFNs and TALENs is through protein-DNA interactions,while RNA-DNA interactions primarily guide Cas9. Cas9 cleavage alsorequires an adjacent motif, the PAM, which differs between differentCRISPR systems. Cas9 from Streptococcus pyogenes cleaves using a NRGPAM, CRISPR from Neisseria meningitidis can cleave at sites with PAMsincluding NNNNGATT, NNNNNGTTT and NNNNGCTT. A number of other Cas9orthologs target protospacer adjacent to alternative PAMs.

CRISPR endonucleases, such as Cas9, can be used in the methods of thepresent disclosure. However, the teachings described herein, such astherapeutic target sites, could be applied to other forms ofendonucleases, such as ZFNs, TALENs, HEs, or MegaTALs, or usingcombinations of nucleases. However, in order to apply the teachings ofthe present disclosure to such endonucleases, one would need to, amongother things, engineer proteins directed to the specific target sites.

Additional binding domains may be fused to the Cas9 protein to increasespecificity. The target sites of these constructs would map to theidentified gRNA specified site, but would require additional bindingmotifs, such as for a zinc finger domain. In the case of Mega-TAL, ameganuclease can be fused to a TALE DNA-binding domain. The meganucleasedomain can increase specificity and provide the cleavage. Similarly,inactivated or dead Cas9 (dCas9) can be fused to a cleavage domain andrequire the sgRNA/Cas9 target site and adjacent binding site for thefused DNA-binding domain. This likely would require some proteinengineering of the dCas9, in addition to the catalytic inactivation, todecrease binding without the additional binding site.

Zinc Finger Nucleases

Zinc finger nucleases (ZFNs) are modular proteins comprised of anengineered zinc finger DNA binding domain linked to the catalytic domainof the type II endonuclease Fold. Because Fold functions only as adimer, a pair of ZFNs must be engineered to bind to cognate target“half-site” sequences on opposite DNA strands and with precise spacingbetween them to enable the catalytically active FokI dimer to form. Upondimerization of the FokI domain, which itself has no sequencespecificity per se, a DNA double-strand break is generated between theZFN half-sites as the initiating step in genome editing.

The DNA binding domain of each ZFN is typically comprised of 3-6 zincfingers of the abundant Cys2-His2 architecture, with each fingerprimarily recognizing a triplet of nucleotides on one strand of thetarget DNA sequence, although cross-strand interaction with a fourthnucleotide also can be important. Alteration of the amino acids of afinger in positions that make key contacts with the DNA alters thesequence specificity of a given finger. Thus, a four-finger zinc fingerprotein will selectively recognize a 12 bp target sequence, where thetarget sequence is a composite of the triplet preferences contributed byeach finger, although triplet preference can be influenced to varyingdegrees by neighboring fingers. An important aspect of ZFNs is that theycan be readily re-targeted to almost any genomic address simply bymodifying individual fingers, although considerable expertise isrequired to do this well. In most applications of ZFNs, proteins of 4-6fingers are used, recognizing 12-18 bp respectively. Hence, a pair ofZFNs will typically recognize a combined target sequence of 24-36 bp,not including the 5-7 bp spacer between half-sites. The binding sitescan be separated further with larger spacers, including 15-17 bp. Atarget sequence of this length is likely to be unique in the humangenome, assuming repetitive sequences or gene homologs are excludedduring the design process. Nevertheless, the ZFN protein-DNAinteractions are not absolute in their specificity so off-target bindingand cleavage events do occur, either as a heterodimer between the twoZFNs, or as a homodimer of one or the other of the ZFNs. The latterpossibility has been effectively eliminated by engineering thedimerization interface of the Fold domain to create “plus” and “minus”variants, also known as obligate heterodimer variants, which can onlydimerize with each other, and not with themselves. Forcing the obligateheterodimer prevents formation of the homodimer. This has greatlyenhanced specificity of ZFNs, as well as any other nuclease that adoptsthese Fold variants.

A variety of ZFN-based systems have been described in the art,modifications thereof are regularly reported, and numerous referencesdescribe rules and parameters that are used to guide the design of ZFNs;see, e.g., Segal et al., Proc Natl Acad Sci USA 96(6):2758-63 (1999);Dreier B et al., J Mol Biol. 303(4):489-502 (2000); Liu Q et al., J BiolChem. 277(6):3850-6 (2002); Dreier et al., J Biol Chem 280(42):35588-97(2005); and Dreier et al., J Biol Chem. 276(31):29466-78 (2001).

Transcription Activator-Like Effector Nucleases (TALENs)

TALENs represent another format of modular nucleases whereby, as withZFNs, an engineered DNA binding domain is linked to the Fold nucleasedomain, and a pair of TALENs operate in tandem to achieve targeted DNAcleavage. The major difference from ZFNs is the nature of the DNAbinding domain and the associated target DNA sequence recognitionproperties. The TALEN DNA binding domain derives from TALE proteins,which were originally described in the plant bacterial pathogenXanthomonas sp. TALEs are comprised of tandem arrays of 33-35 amino acidrepeats, with each repeat recognizing a single basepair in the targetDNA sequence that is typically up to 20 bp in length, giving a totaltarget sequence length of up to 40 bp. Nucleotide specificity of eachrepeat is determined by the repeat variable diresidue (RVD), whichincludes just two amino acids at positions 12 and 13. The bases guanine,adenine, cytosine and thymine are predominantly recognized by the fourRVDs: Asn-Asn, Asn-Ile, His-Asp and Asn-Gly, respectively. Thisconstitutes a much simpler recognition code than for zinc fingers, andthus represents an advantage over the latter for nuclease design.Nevertheless, as with ZFNs, the protein-DNA interactions of TALENs arenot absolute in their specificity, and TALENs have also benefitted fromthe use of obligate heterodimer variants of the Fold domain to reduceoff-target activity.

Additional variants of the Fold domain have been created that aredeactivated in their catalytic function. If one half of either a TALENor a ZFN pair contains an inactive Fold domain, then only single-strandDNA cleavage (nicking) will occur at the target site, rather than a DSB.The outcome is comparable to the use of CRISPR/Cas9/Cpf1 “nickase”mutants in which one of the Cas9 cleavage domains has been deactivated.DNA nicks can be used to drive genome editing by HDR, but at lowerefficiency than with a DSB. The main benefit is that off-target nicksare quickly and accurately repaired, unlike the DSB, which is prone toNHEJ-mediated mis-repair.

A variety of TALEN-based systems have been described in the art, andmodifications thereof are regularly reported; see, e.g., Boch, Science326(5959):1509-12 (2009); Mak et al., Science 335(6069):716-9 (2012);and Moscou et al., Science 326(5959):1501 (2009). The use of TALENsbased on the “Golden Gate” platform, or cloning scheme, has beendescribed by multiple groups; see, e.g., Cermak et al., Nucleic AcidsRes. 39(12):e82 (2011); Li et al., Nucleic Acids Res.39(14):6315-25(2011); Weber et al., PLoS One. 6(2):e16765 (2011); Wanget al., J Genet Genomics 41(6):339-47, Epub 2014 May 17 (2014); andCermak T et al., Methods Mol Biol. 1239:133-59 (2015).

Homing Endonucleases

Homing endonucleases (HEs) are sequence-specific endonucleases that havelong recognition sequences (14-44 base pairs) and cleave DNA with highspecificity—often at sites unique in the genome. There are at least sixknown families of HEs as classified by their structure, includingLAGLIDADG (SEQ ID NO: 4), GIY-YIG (SEQ ID NO: 5), His-Cis box, H-N-H,PD-(D/E)xK (SEQ ID NO: 6), and Vsr-like that are derived from a broadrange of hosts, including eukarya, protists, bacteria, archaea,cyanobacteria and phage. As with ZFNs and TALENs, HEs can be used tocreate a DSB at a target locus as the initial step in genome editing. Inaddition, some natural and engineered HEs cut only a single strand ofDNA, thereby functioning as site-specific nickases. The large targetsequence of HEs and the specificity that they offer have made themattractive candidates to create site-specific DSBs.

A variety of HE-based systems have been described in the art, andmodifications thereof are regularly reported; see, e.g., the reviews bySteentoft et al., Glycobiology 24(8):663-80 (2014); Belfort andBonocora, Methods Mol Biol. 1123:1-26 (2014); Hafez and Hausner, Genome55(8):553-69 (2012); and references cited therein.

MegaTAL/Tev-mTALEN/MegaTev

As further examples of hybrid nucleases, the MegaTAL platform andTev-mTALEN platform use a fusion of TALE DNA binding domains andcatalytically active HEs, taking advantage of both the tunable DNAbinding and specificity of the TALE, as well as the cleavage sequencespecificity of the HE; see, e.g., Boissel et al., NAR 42: 2591-2601(2014); Kleinstiver et al., G3 4:1155-65 (2014); and Boissel andScharenberg, Methods Mol. Biol. 1239: 171-96 (2015).

In a further variation, the MegaTev architecture is the fusion of ameganuclease (Mega) with the nuclease domain derived from the GIY-YIGhoming endonuclease I-TevI (Tev). The two active sites are positioned˜30 bp apart on a DNA substrate and generate two DSBs withnon-compatible cohesive ends; see, e.g., Wolfs et al., NAR 42, 8816-29(2014). It is anticipated that other combinations of existingnuclease-based approaches will evolve and be useful in achieving thetargeted genome modifications described herein.

dCas9-FokI or dCpf1-FokI and Other Nucleases

Combining the structural and functional properties of the nucleaseplatforms described above offers a further approach to genome editingthat can potentially overcome some of the inherent deficiencies. As anexample, the CRISPR genome editing system typically uses a single Cas9endonuclease to create a DSB. The specificity of targeting is driven bya 20 or 22 nucleotide sequence in the guide RNA that undergoesWatson-Crick base-pairing with the target DNA (plus an additional 2bases in the adjacent NAG or NGG PAM sequence in the case of Cas9 fromS. pyogenes). Such a sequence is long enough to be unique in the humangenome, however, the specificity of the RNA/DNA interaction is notabsolute, with significant promiscuity sometimes tolerated, particularlyin the 5′ half of the target sequence, effectively reducing the numberof bases that drive specificity. One solution to this has been tocompletely deactivate the Cas9 or Cpf1 catalytic function—retaining onlythe RNA-guided DNA binding function—and instead fusing a FokI domain tothe deactivated Cas9; see, e.g., Tsai et al., Nature Biotech 32: 569-76(2014); and Guilinger et al., Nature Biotech. 32: 577-82 (2014). BecauseFold must dimerize to become catalytically active, two guide RNAs arerequired to tether two Fold fusions in close proximity to form the dimerand cleave DNA. This essentially doubles the number of bases in thecombined target sites, thereby increasing the stringency of targeting byCRISPR-based systems.

As further example, fusion of the TALE DNA binding domain to acatalytically active HE, such as I-TevI, takes advantage of both thetunable DNA binding and specificity of the TALE, as well as the cleavagesequence specificity of I-TevI, with the expectation that off-targetcleavage may be further reduced.

Additional Aspects

Provided herein are nucleic acids, vectors, cells, methods, and othermaterials for use in ex vivo and in vivo methods for creating permanentchanges to the genome by deleting, inserting, or modulating theexpression of or function of one or more nucleic acids or exons withinor near a target gene or other DNA sequences that encode regulatoryelements of the target gene or knocking in a cDNA, expression vector, orminigene, which may be used to treat a medical condition such as, by wayof non-limiting example, cancer, inflammatory disease and/or autoimmunedisease. Also provided herein are components, kits, and compositions forperforming such methods. Also provided are cells produced by suchmethods.

The following paragraphs are also encompassed by the present disclosure:

1. An isolated nucleic acid encoding a knock-in chimeric antigenreceptor (CAR) construct, wherein the knock-in CAR construct comprises apolynucleotide donor template comprising at least a portion of a targetgene operably linked to a nucleic acid encoding a chimeric antigenreceptor (CAR) comprising: (i) an ectodomain comprising an antigenrecognition region; (ii) a transmembrane domain, and (iii) an endodomaincomprising at least one costimulatory domain.2. The isolated nucleic acid of paragraph 1, further comprising apromoter, one or more gene regulatory elements, or a combinationthereof.3. The isolated nucleic acid of paragraph 2, wherein the one or moregene regulatory elements are selected from the group consisting of anenhancer sequence, an intron sequence, a polyadenylation (poly(A))sequence, and combinations thereof.4. The isolated nucleic acid of any one of paragraphs 1 to 3, whereinthe target gene comprises a gene sequence associated with host versusgraft response, a gene sequence associated with graft versus hostresponse, a gene sequence encoding a checkpoint inhibitor, or anycombination thereof.5. The isolated nucleic acid of paragraph 4, wherein the gene sequenceassociated with a graft versus host response is selected from the groupconsisting of TRAC, CD3-epsilon (CD3ε), and combinations thereof.6. The isolated nucleic acid of paragraph 4, wherein the gene sequenceassociated with a host versus graft response is selected from the groupconsisting of B2M, CIITA, RFX5, and combinations thereof.7. The isolated nucleic acid of paragraph 4, wherein the gene sequenceencoding a checkpoint inhibitor is selected from the group consisting ofPD1, CTLA-4, and combinations thereof.8. The isolated nucleic acid of any one of paragraphs 1 to 3, whereinthe target gene comprises a sequence associated with pharmacologicalmodulation of a cell.9. The isolated nucleic acid of paragraph 8, wherein the target gene isCD52.10. The isolated nucleic acid of paragraph 8, wherein the modulation ispositive or negative.11. The isolated nucleic acid of paragraph 8, wherein the modulationallows the CAR T cells to survive.12. The isolated nucleic acid of paragraph 8, wherein the modulationkills the CAR T cells.13. The isolated nucleic acid of paragraph 1, further comprising aminigene or cDNA.14. The isolated nucleic acid of paragraph 13, wherein the minigene orcDNA comprises a gene sequence associated with pharmacologicalmodulation of a cell.15. The isolated nucleic acid of paragraph 14, wherein the gene sequenceencodes Her2.16. The isolated nucleic acid of paragraph 4, wherein the target genecomprises a gene selected from the group consisting of TRAC, CD3ε, B2M,CIITA, RFX5, PD1, CTLA-4, CD52, PPP1R12C, and combinations thereof.17. The isolated nucleic acid of paragraph 4, wherein the target genecomprises a gene selected from the group consisting of TRAC, B2M andPD1.18. The isolated nucleic acid of paragraph 4, wherein the target genecomprises two or more genes selected from the group consisting of TRAC,CD3ε, B2M, CIITA, RFX5, PD1, CTLA-4, CD52, PPP1R12C, and combinationsthereof.19. The isolated nucleic acid of paragraph 4, wherein the target genecomprises two or more genes selected from the group consisting of TRAC,B2M and PD1.20. The isolated nucleic acid of any one of paragraphs 1 to 19, whereinthe donor template is either a single or double stranded polynucleotide.21. The isolated nucleic acid of paragraph 20, wherein the portion ofthe target gene is selected from the group consisting of TRAC, CD3ε,B2M, CIITA, RFX5, PD1, CTLA-4, CD52, PPP1R12C, and combinations thereof.22. The isolated nucleic acid of paragraph 20, wherein the portion ofthe target gene comprises a portion of TRAC, a portion of B2M, and/or aportion of PD1.23. The isolated nucleic acid of any one of paragraphs 1 to 22, whereinthe antigen recognition domain recognizes CD19, BCMA, CD70, orcombinations thereof.24. The isolated nucleic acid of any one of paragraphs 1 to 22, whereinthe antigen recognition domain recognizes CD19.25. The isolated nucleic acid of any one of paragraphs 1 to 22, whereinthe antigen recognition domain recognizes CD70.26. The isolated nucleic acid of any one of paragraphs 1 to 22, whereinthe antigen recognition domain recognizes BCMA.27. The isolated nucleic acid of any one of paragraphs 1 to 26, whereinthe antigen recognition domain is a scFV.28. The isolated nucleic acid of paragraph 27, wherein the scFV is ananti-CD19 scFv encoded by a nucleic acid sequence comprising SEQ ID NO:1333 or an amino acid sequence comprising SEQ ID NO: 1334.29. The isolated nucleic acid of paragraph 27, wherein the scFV is ananti-CD70 scFv

1) encoded by a nucleic acid sequence comprising SEQ ID NO: 1475 or anamino acid sequence comprising SEQ ID NO: 1499 or

2) encoded by a nucleic acid sequence comprising SEQ ID NO: 1476 or anamino acid sequence comprising SEQ ID NO: 1500.

30. The isolated nucleic acid of paragraph 27, wherein the scFV is ananti-BCMA scFv

1) encoded by a nucleic acid sequence comprising SEQ ID NO: 1477-1498 oran amino acid sequence comprising SEQ ID NO: 1501-1522 or

2) encoded by a nucleic acid sequence comprising SEQ ID NO: 1485 or anamino acid sequence comprising SEQ ID NO: 1509.

31. The isolated nucleic acid of any one of paragraphs 1 to 30, whereinthe costimulatory domain comprises a CD28 co-stimulatory domain or a4-1BB co-stimulatory domain.

32. The isolated nucleic acid of any one of paragraphs 1 to 31, whereinthe endodomain further comprises a CD3-zeta (CD3) domain.

33. The isolated nucleic acid of any one of paragraphs 1 to 32, whereinthe ectodomain further comprises a signal peptide.

34. The isolated nucleic acid of any one of paragraphs 1 to 33, whereinthe ectodomain further comprises a hinge between the antigen recognitionregion and the transmembrane domain.

35. The isolated nucleic acid of paragraph 34, wherein the hingecomprises a CD8 hinge region.

36. The isolated nucleic acid of any one of paragraphs 1 to 35, whereinthe antigen recognition domain is a single chain variable fragment(scFv), wherein the hinge region comprises a CD8 hinge region, andwherein the endodomain comprises a CD28 costimulatory domain and a CD3ζdomain, or a 4-1BB co-stimulatory domain and a CD3ζ domain.38. The isolated nucleic acid of any one of paragraphs 1 to 36, whereinthe CAR construct has the following structural arrangement fromN-terminus to C-terminus: antigen recognition domain scFv+CD8hinge+transmembrane domain+CD28 costimulatory domain+CD3ζ domain, orantigen recognition domain scFv+CD8 hinge+transmembrane domain+4-1BBcostimulatory domain+CD3ζ domain.39. The isolated nucleic acid of any of paragraphs 1 to 38, wherein thedonor template sequence comprises a sequence selected from the groupconsisting of SEQ ID NOs: 1387-1422.40. The isolated nucleic acid of any of paragraphs 1 to 38, wherein thedonor template sequence comprises the sequence of SEQ ID NO: 1390.41. The isolated nucleic acid of any of paragraphs 1 to 38, wherein thedonor template sequence comprises a sequence selected from the groupconsisting of SEQ ID NOs: 1394-1396.42. The isolated nucleic acid of any of paragraphs 1 to 38, wherein thedonor template sequence comprises a sequence selected from the groupconsisting of SEQ ID NOs: 1397-1422, for example, SEQ ID NOs: 1398,1401, 1402, 1408, or 1409.43. A vector comprising the isolated nucleic acid of any one ofparagraphs 1 to 42.44. The vector of paragraph 42, wherein the vector is an AAV.45. The vector of paragraph 43 or 44, wherein the AAV vector is an AAV6vector.46. The vector of paragraph 43 or 44, wherein the vector comprises a DNAsequence selected from the group consisting of SEQ ID NO: 1348-1386.47. The vector of paragraph 43 or 44, wherein the vector comprises a DNAsequence of SEQ ID NO: 1354.48. The vector of paragraph 42 or 43, wherein the vector comprises a DNAsequence selected from the group consisting of SEQ ID NO: 1358-1360.49. The vector of paragraph 42 or 43, wherein the vector comprises a DNAsequence selected from the group consisting of SEQ ID NO: 1362, 1365,1366, 1372, and 1373.50. An isolated cell comprising the vector of any of paragraphs 43-49.51. The isolated cell of paragraph 50, wherein the cell is a T cell.52. The isolated cell of paragraph 51, wherein the T-cell is a CD4⁺T-cell, a CD8⁺ T-cell, or a combination thereof.53. One or more guide ribonucleic acids (gRNAs) for editing a gene, theone or more gRNAs selected from the group consisting of:

(a) one or more gRNAs for editing a TRAC gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 83-158;

(b) one or more gRNAs for editing a B2M gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 458-506;

(c) one or more gRNAs for editing a CIITA gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 699-890;

(d) one or more gRNAs for editing a CD3ε gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 284-408; or

(e) one or more gRNAs for editing a PD1 gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 1083-1274.

54. The one or more gRNAs of paragraph 53, wherein the one or more gRNAsare one or more single-molecule guide RNAs (sgRNAs).

55. The one or more gRNAs or sgRNAs of paragraph 53 or 54, wherein theone or more gRNAs or one or more sgRNAs is one or more modified gRNAs orone or more modified sgRNAs.

56. A ribonucleoprotein particle comprising the one or more gRNAs orsgRNAs of any one of paragraphs 53-55 and one or more site-directedpolypeptides.

57. The ribonucleoprotein particle of paragraph 56, wherein the one ormore site-directed polypeptides is one or more deoxyribonucleic acid(DNA) endonucleases.

58. The ribonucleoprotein particle of paragraph 57, wherein the one ormore DNA endonucleases is a Cas9 or Cpf1 endonuclease; or a homologthereof, recombination of the naturally occurring molecule,codon-optimized, or modified version thereof, and combinations thereof.59. The ribonucleoprotein particle of paragraph 57 or 58, wherein theone or more DNA endonucleases is pre-complexed with one or more gRNAs orone or more sgRNAs.60. A composition comprising the isolated nucleic acid of any one ofparagraphs 1-42 and one or more ribonucleoprotein particles of any oneof paragraphs 56-59.61. The composition of paragraph 60, wherein the target gene is a TRACgene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a TRAC gene.62. The composition of paragraph 60, wherein the target gene is a B2Mgene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a B2M gene.63. The composition of paragraph 60, wherein the target gene is a PD1gene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a PD1 gene.64. The composition of paragraph 60, wherein the target gene is a TRACgene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a TRAC gene.65. The composition of paragraph 60, wherein the target gene is a B2Mgene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a B2M gene.66. The composition of paragraph 60, wherein the target gene is a PD1gene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a PD1 gene.67. The composition of paragraph 60, wherein the target gene is a TRACgene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a TRAC gene.68. The composition of paragraph 60, wherein the target gene is a B2Mgene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a B2M gene.69. The composition of paragraph 60, wherein the target gene is a PD1gene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a PD1 gene.70. The composition of any one of paragraphs 61-69, wherein the donortemplate is either a single or double stranded polynucleotide.71. The composition of any one of paragraphs 60, 61, 64, 67 or 70,wherein the one or more ribonucleoprotein particles comprises one ormore DNA endonucleases and one or more gRNAs for editing a TRAC gene,the one or more gRNAs comprising a spacer sequence selected from thegroup consisting of the nucleic acid sequences of SEQ ID NOs: 83-158.72. The composition of any one of paragraphs 60, 62, 65, 68 or 70,wherein the one or more ribonucleoprotein particles comprises one ormore DNA endonucleases and one or more gRNAs for editing a B2M gene, theone or more gRNAs comprising a spacer sequence selected from the groupconsisting of the nucleic acid sequences of SEQ ID NOs: 458-506.73. The composition of any one of paragraphs 60, 63, 66, 69 or 70,wherein the one or more ribonucleoprotein particles comprises one ormore DNA endonucleases and one or more gRNAs for editing a PD1 gene, theone or more gRNAs comprising a spacer sequence selected from the groupconsisting of the nucleic acid sequences of SEQ ID NOs: 1083-1274.74. The composition of paragraph 71 or 73, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a B2M gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 458-506.75. The composition of paragraph 71 or 72, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a PD1 gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 1083-1274.76. The composition of paragraph 72 or 73, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a TRAC gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 83-158.77. A composition comprising the vector of any one of paragraphs 43-49,and one or more ribonucleoprotein particles of any one of paragraphs56-59.78. The composition of paragraph 77, wherein the target gene is a TRACgene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a TRAC gene.79. The composition of paragraph 77, wherein the target gene is a B2Mgene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a B2M gene.80. The composition of paragraph 77, wherein the target gene is a PD1gene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a PD1 gene.81. The composition of paragraph 77, wherein the target gene is a TRACgene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a TRAC gene.82. The composition of paragraph 77, wherein the target gene is a B2Mgene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a B2M gene.83. The composition of paragraph 77, wherein the target gene is a PD1gene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a PD1 gene.84. The composition of paragraph 77, wherein the target gene is a TRACgene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a TRAC gene.85. The composition of paragraph 77, wherein the target gene is a B2Mgene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a B2M gene.86. The composition of paragraph 77, wherein the target gene is a PD1gene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a PD1 gene.87. The composition of paragraph any one of paragraphs 78-86, whereinthe donor template is either a single or double stranded polynucleotide.88. The composition of any one of paragraphs 77, 78, 81, 84 or 87,wherein the one or more ribonucleoprotein particles comprises one ormore DNA endonucleases and one or more gRNAs for editing a TRAC gene,the one or more gRNAs comprising a spacer sequence selected from thegroup consisting of the nucleic acid sequences of SEQ ID NOs: 83-158.89. The composition of any one of paragraphs 77, 79, 82, 85 or 87,wherein the one or more ribonucleoprotein particles comprises one ormore DNA endonucleases and one or more gRNAs for editing a B2M gene, theone or more gRNAs comprising a spacer sequence selected from the groupconsisting of the nucleic acid sequences of SEQ ID NOs: 458-506.90. The composition of any one of paragraphs 77, 80, 83, 86 or 87,wherein the one or more ribonucleoprotein particles comprises one ormore DNA endonucleases and one or more gRNAs for editing a PD1 gene, theone or more gRNAs comprising a spacer sequence selected from the groupconsisting of the nucleic acid sequences of SEQ ID NOs: 1083-1275.91. The composition of paragraph 88 or 90, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a B2M gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 458-506.92. The composition of paragraph 88 or 89, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a PD1 gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 1083-1275.93. The composition of paragraph 89 or 90, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a TRAC gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 83-158.94. The composition of any one of paragraphs 77, 78, 81, 84, 87, 88 or93, wherein the donor template comprises a sequence selected from thegroup consisting of SEQ ID NOs: 1387 and 1390 and the gRNA is an sgRNAfor editing a TRAC gene comprising the sequence of SEQ ID NO: 1342 or1343.95. The composition of any one of paragraphs 77, 78, 81, 84, 87, 88 or93, wherein the donor template comprises a sequence selected from thegroup consisting of SEQ ID NOs: 1394-1396 and the gRNA is an sgRNA forediting a TRAC gene comprising the sequence of SEQ ID NO: 1342 or 1343.96. The composition of any one of paragraphs 77, 78, 81, 84, 87, 88 or93, wherein the donor template comprises a sequence selected from thegroup consisting of SEQ ID NOs: 1398, 1400, 1401, 1402, 1408, and 1409and the gRNA is an sgRNA for editing a TRAC gene comprising the sequenceof SEQ ID NO: 1342 or 1343.97. The composition of any one of paragraphs 94-96, further comprisingan sgRNA for editing a B2M gene comprising the sequence of SEQ ID NO:1344 or 1345.98. The composition of any one of paragraphs 77, 79, 82, 85, 87, 89, 91,wherein the donor template comprises a sequence selected from the groupconsisting of SEQ ID NOs: 1387 and 1390 and the gRNA is an sgRNA forediting a B2M gene comprising the sequence of SEQ ID NO: 1342 or 1343.99. The composition of any one of paragraphs 77, 79, 82, 85, 87, 89, 91,wherein the donor template comprises a sequence selected from the groupconsisting of SEQ ID NOs: 1394 and 1395 and the gRNA is an sgRNA forediting a B2M gene comprising the sequence of SEQ ID NO: 1342 or 1343.100. The composition of any one of paragraphs 77, 79, 82, 85, 87, 89,91, wherein the donor template comprises a sequence selected from thegroup consisting of SEQ ID NOs: 1398 and 1400 and the gRNA is an sgRNAfor editing a B2M gene comprising the sequence of SEQ ID NO: 1342 or1343.101. An isolated cell comprising the isolated nucleic acid of any one ofparagraphs 1-42, and one or more ribonucleoprotein particles of any oneof paragraphs 56-59.102. The isolated cell of paragraph 101, wherein the target gene is aTRAC gene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a TRAC gene.103. The isolated cell of paragraph 101, wherein the target gene is aB2M gene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a B2M gene.104. The isolated cell of paragraph 101, wherein the target gene is aPD1 gene, the antigen recognition region recognizes CD19, and the donortemplate comprises at least a portion of a PD1 gene.105. The isolated cell of paragraph 101, wherein the target gene is aTRAC gene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a TRAC gene.106. The isolated cell of paragraph 101, wherein the target gene is aB2M gene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a B2M gene.107. The isolated cell of paragraph 101, wherein the target gene is aPD1 gene, the antigen recognition region recognizes CD70, and the donortemplate comprises at least a portion of a PD1 gene.108. The isolated cell of paragraph 101, wherein the target gene is aTRAC gene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a TRAC gene.109. The isolated cell of paragraph 101, wherein the target gene is aB2M gene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a B2M gene.110. The isolated cell of paragraph 101, wherein the target gene is aPD1 gene, the antigen recognition region recognizes BCMA, and the donortemplate comprises at least a portion of a PD1 gene.111. The isolated cell of any one of paragraphs 102-110, wherein thedonor template is either a single or double stranded polynucleotide.112. The isolated cell of any one of paragraphs 101, 102, 105, 108 or111, wherein the one or more ribonucleoprotein particles comprises oneor more DNA endonucleases and one or more gRNAs for editing a TRAC gene,the one or more gRNAs comprising a spacer sequence selected from thegroup consisting of the nucleic acid sequences of SEQ ID NOs: 83-158.113. The isolated cell of any one of paragraphs 101, 103, 106, 109 or111, wherein the one or more ribonucleoprotein particles comprises oneor more DNA endonucleases and one or more gRNAs for editing a B2M gene,the one or more gRNAs comprising a spacer sequence selected from thegroup consisting of the nucleic acid sequences of SEQ ID NOs: 458-506.114. The isolated cell of any one of paragraphs 101, 104, 107, 110 or111, wherein the one or more ribonucleoprotein particles comprises oneor more DNA endonucleases and one or more gRNAs for editing a PD1 gene,the one or more gRNAs comprising a spacer sequence selected from thegroup consisting of the nucleic acid sequences of SEQ ID NOs: 1083-1274.115. The isolated cell of paragraph 112 or 114, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a B2M gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 458-506.116. The isolated cell of paragraph 112 or 113, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a PD1 gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 1083-1274.117. The isolated cell of paragraph 113 or 114, wherein the one or moreribonucleoprotein particles further comprises one or more gRNAs forediting a TRAC gene, the one or more gRNAs comprising a spacer sequenceselected from the group consisting of the nucleic acid sequences of SEQID NOs: 83-158.118. The isolated cell of any one of paragraphs 101-118, wherein the oneor more ribonucleoprotein particles comprises two or more differentpopulations of ribonucleoprotein particles.119. The isolated cell of paragraph 118, wherein the wherein the one ormore ribonucleoprotein particles comprises one or more DNA endonucleasesand two or more different populations of ribonucleoprotein particlesselected from the group consisting of:

(a) one or more gRNAs for editing a TRAC gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 83-158;

(b) one or more gRNAs for editing a B2M gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 458-506;

(c) one or more gRNAs for editing a CIITA gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 699-890 for editing the CIITAgene;

(d) one or more gRNAs for editing a CD3ε gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 284-408;

(e) one or more gRNAs for editing a PD1 gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 1083-1274;

(f) one or more gRNAs for editing a TRAC gene, the one or more gRNAscomprising a spacer sequence comprising the nucleic acid sequence of SEQID NO: 1299;

(g) one or more gRNAs for editing a CTLA-4 gene, the one or more gRNAscomprising a spacer sequence comprising the nucleic acid sequence of SEQID NO: 1277;

(h) one or more gRNAs for editing a AAVS1 (PPP1R12C) gene the one ormore gRNAs comprising a spacer sequence selected from the groupconsisting of the nucleic acid sequences of SEQ ID NOs: 1301-1302;

(i) one or more gRNAs for editing a CD52 gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 1303-1304; and

(j) one or more gRNAs for editing a RFX5 gene, the one or more gRNAscomprising a spacer sequence selected from the group consisting of thenucleic acid sequences of SEQ ID NOs: 1305-1307.

120. An isolated cell comprising the isolated nucleic acid of and one ofparagraph 1-42 and a first population of one or more ribonucleoproteinparticles of any one of paragraphs 56-59, wherein the isolated nucleicacid is inserted into the genome at a locus within or near a firsttarget gene that results is a permanent deletion within or near thefirst target gene and insertion of the isolated nucleic acid encodingthe CAR.121. The isolated cell of paragraph 120, wherein the isolated cellfurther comprises a second population of one or more ribonucleoproteinparticles of any one of paragraphs 56-59, wherein the first populationof one or more ribonucleoprotein particles comprises one or more gRNAsfor editing a first target gene and the second population of one or moreribonucleoprotein particles comprises one or more gRNAs for editing asecond, different target gene.122. An isolated cell, expressing a chimeric antigen receptor encoded bythe nucleic acid of any one of paragraphs 1-42 and comprising a deletionin one or more genes selected from: TRAC, CD3ε, B2M, CIITA, RFX5, PD1,and CTLA-4.123. An isolated cell, expressing a chimeric antigen receptor encoded bythe nucleic acid of any one of paragraphs 1-42 and comprising a deletionin one or more of TRAC, B2M and PD1.124. An isolated cell, expressing a chimeric antigen receptor encoded bythe nucleic acid of any one of paragraphs 1-42 and comprising a deletionin TRAC.125. The isolated cell of paragraph 124, further comprising a deletionin B2M.126. The isolated cell of paragraph 124, further comprising a deletionin B2M and PD1.127. The isolated cell of any one of paragraphs 101-126, wherein thechimeric antigen receptor is expressed from the TRAC locus.128. The isolated cell of paragraph 127, wherein the chimeric antigenreceptor comprises a sequence selected from the group consisting of SEQID NO: 1334, 1499, 1500, 1501, and 1502.129. The isolated cell of paragraph 127, wherein the chimeric antigenreceptor (CAR) comprises a sequence encoding the CAR selected from thegroup consisting of SEQ ID NO: 1316, 1423, 1424, 1425 and 1426.130. The isolated cell of paragraph 127, wherein the chimeric antigenreceptor (CAR) comprises an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1338, 1449, 1450, 1451 and 1452.131. An isolated cell transfected with the vector comprising a nucleicacid selected from the group consisting of: SEQ ID Nos: 1348, 1354,1358, 1359, 1362 and 1364 and further comprising a deletion in one ormore genes selected from: TRAC, CD3ε, B2M, CIITA, RFX5, PD1, and CTLA-4.132. An isolated cell transfected with the vector comprising a nucleicacid selected from the group consisting of: SEQ ID Nos: 1348, 1354,1358, 1359, 1362 and 1364 and further comprising a deletion in TRAC.133. An isolated cell transfected with the vector comprising a nucleicacid selected from the group consisting of: SEQ ID Nos: 1348, 1354,1358, 1359, 1362 and 1364 and further comprising a deletion in TRAC andB2M.134. An isolated cell transfected with the vector comprising a nucleicacid selected from the group consisting of: SEQ ID Nos: 1348, 1354,1358, 1359, 1362 and 1364 and further comprising a deletion in TRAC, B2Mand PD1.135. The isolated cell of any one of paragraphs 127-134, wherein thenucleic acid sequence comprises a donor template that is permanentlyinserted in the TRAC gene, disrupting TRAC gene expression.136. The isolated cell of paragraph 135, further comprising a deletionin the B2M gene.137. The isolated cell of paragraph 136, further comprising a deletionin the PD1 gene.138. The isolated cell of any one of paragraphs 131-137, wherein:

-   -   a) one or more ribonucleoprotein particles effect one or more        single-strand breaks or double-strand breaks in the TRAC target        gene resulting a permanent deletion in the TRAC gene, wherein        the ribonucleoprotein particles comprise one or more sgRNAs        comprising a sequence SEQ ID NO: 1342 or 1343 and one or more        deoxyribonucleic acid (DNA) endonucleases; and    -   b) one or more ribonucleoprotein particles effect one or more        single-strand breaks or double-strand breaks in the B2M target        gene resulting a permanent deletion in the B2M gene, wherein the        ribonucleoprotein particles comprise one or more sgRNAs        comprising a sequence of SEQ ID NO: 1344 or 1345 and one or more        deoxyribonucleic acid (DNA) endonucleases        139. An isolated cell comprising:    -   a) the isolated nucleic acid of any one of paragraph 1-42,        wherein the isolated nucleic acid is inserted into the genome by        homologous recombination at a locus within or near a TRAC gene        that results is a permanent deletion within or near the TRAC        gene;    -   b) a permanent deletion within or near a second target gene,        wherein the second target gene is B2M;    -   c) insertion of the isolated nucleic acid encoding the CAR into        the TRAC gene, wherein the CAR comprises a CD19 antigen        recognition domain; and    -   d) the CAR is expressed on the surface of the cell.        140. An isolated cell comprising:    -   a) the isolated nucleic acid of any one of paragraphs 1-42,        wherein the isolated nucleic acid is inserted into the genome by        homologous recombination at a locus within or near a TRAC gene        that results is a permanent deletion within or near the TRAC        gene;    -   b) a permanent deletion within or near a second target gene,        wherein the second target gene is B2M;    -   c) insertion of the isolated nucleic acid encoding the CAR into        the TRAC gene, wherein the CAR comprises a CD70 antigen        recognition domain; and    -   d) the CAR is expressed on the surface of the cell.        141. An isolated cell comprising:    -   a) the isolated nucleic acid of any one of paragraphs 1-42,        wherein the isolated nucleic acid is inserted into the genome by        homologous recombination at a locus within or near a TRAC gene        that results is a permanent deletion within or near the TRAC        gene;    -   b) a permanent deletion within or near a second target gene,        wherein the second target gene is B2M;    -   c) insertion of the isolated nucleic acid encoding the CAR into        the TRAC gene, wherein the CAR comprises a BCMA antigen        recognition domain; and    -   d) the CAR is expressed on the surface of the cell.        142. The isolated cell of any one of paragraphs 139-141, further        comprising a permanent deletion within or near a third target        gene, wherein the third target gene is PD1.        143. The isolated cell of any one of paragraphs 139-142,        wherein:    -   a) the isolated nucleic acid comprises a nucleotide sequence of        SEQ ID Nos: 1348, 1354, 1358, 1359, 1362 and 1364;    -   b) one or more gRNAs comprise a spacer sequence selected from        SEQ ID Nos: 83-158 and one or more deoxyribonucleic acid (DNA)        endonucleases, effect one or more single-strand breaks or        double-strand breaks in the TRAC gene resulting a permanent        deletion in the TRAC gene; and    -   c) one or more gRNAs comprising a spacer sequence selected from        SEQ ID Nos: 458-506 and one or more deoxyribonucleic acid (DNA)        endonucleases, effect one or more single-strand breaks or        double-strand breaks in the B2M gene resulting a permanent        deletion in the B2M gene.        144. The isolated cell of paragraph 143, wherein:    -   a) the isolated nucleic acid comprises a nucleotide sequence is        selected from the group consisting of SEQ ID NO: 1348-1357;    -   b) one or more ribonucleoprotein particles effect one or more        single-strand breaks or double-strand breaks in the TRAC target        gene resulting a permanent deletion in the TRAC target gene,        wherein the ribonucleoprotein particles comprise one or more        sgRNAs comprising a sequence SEQ ID NO: 1342 or 1343 and one or        more deoxyribonucleic acid (DNA) endonucleases; and    -   c) one or more ribonucleoprotein particles effect one or more        single-strand breaks or double-strand breaks in the B2M target        gene resulting a permanent deletion in the B2M target gene,        wherein the ribonucleoprotein particles comprise one or more        sgRNAs comprising a sequence of SEQ ID NO: 1344 or 1345 and one        or more deoxyribonucleic acid (DNA) endonucleases.        145. The isolated cell of paragraph 143, wherein:    -   a) the isolated nucleic acid comprises a nucleotide sequence is        selected from the group consisting of SEQ ID NO: 1358 and 1359;    -   b) one or more ribonucleoprotein particles effect one or more        single-strand breaks or double-strand breaks in the TRAC target        gene resulting a permanent deletion in the TRAC target gene,        wherein the ribonucleoprotein particles comprise one or more        sgRNAs comprising a sequence SEQ ID NO: 1342 or 1343 and one or        more deoxyribonucleic acid (DNA) endonucleases; and    -   c) one or more ribonucleoprotein particles effect one or more        single-strand breaks or double-strand breaks in the B2M target        gene resulting a permanent deletion in the B2M target gene,        wherein the ribonucleoprotein particles comprise one or more        sgRNAs comprising a sequence of SEQ ID NO: 1344 or 1345 and one        or more deoxyribonucleic acid (DNA) endonucleases.        146. The isolated cell of paragraph 143, wherein:    -   a) the isolated nucleic acid comprises a nucleotide sequence is        selected from the group consisting of SEQ ID NO: 1362 and 1364;    -   b) one or more ribonucleoprotein particles effect one or more        single-strand breaks or double-strand breaks in the TRAC target        gene resulting a permanent deletion in the TRAC target gene,        wherein the ribonucleoprotein particles comprise one or more        sgRNAs comprising a sequence SEQ ID NO: 1342 or 1343 and one or        more deoxyribonucleic acid (DNA) endonucleases; and    -   c) one or more ribonucleoprotein particles effect one or more        single-strand breaks or double-strand breaks in the B2M target        gene resulting a permanent deletion in the B2M target gene,        wherein the ribonucleoprotein particles comprise one or more        sgRNAs comprising a sequence of SEQ ID NO: 1344 or 1345 and one        or more deoxyribonucleic acid (DNA) endonucleases.        147. A pharmaceutical composition comprising the isolated cell        of any one of paragraphs 101-146.        148. A method for producing a gene edited cell, the method        comprising the steps of: introducing into the cell (i) the        isolated nucleic acid encoding a knock-in chimeric antigen        receptor (CAR) construct of any one of paragraphs 1-42, (ii) one        or more sgRNA and (iii) one or more deoxyribonucleic acid (DNA)        endonucleases to effect one or more single-strand breaks (SSBs)        or double-strand breaks (DSBs) within or near a first target        gene that results in: a) a permanent deletion within or near the        first target gene affecting the expression or function of the        first target gene, optionally wherein the permanent deletion is        in the PAM or sgRNA target sequence, and optionally wherein the        permanent deletion is a 20 nucleotide deletion, b) insertion of        the CAR construct within or near the first target gene, and, c)        expression of the CAR on the surface of a cell.        149. A method for modulating one or more biological activities        of a cell, the method comprising the step of:        introducing into the cell (i) the isolated nucleic acid encoding        a knock-in chimeric antigen receptor (CAR) construct of any one        of paragraphs 1-42, (ii) one or more sgRNA and (iii) one or more        deoxyribonucleic acid (DNA) endonucleases to effect one or more        single-strand breaks (SSBs) or double-strand breaks (DSBs)        within or near a first target gene that results in: a) a        permanent deletion within or near the first target gene        affecting the expression or function of the first target gene,        optionally wherein the permanent deletion is in the PAM or sgRNA        target sequence, and optionally wherein the permanent deletion        is a 20 nucleotide deletion, b) insertion of the CAR construct        within or near the first target gene, and, c) expression of the        CAR on the surface of a cell.        150. The method of paragraph 148 or 149, wherein the gRNA and        endonuclease form a ribonucleoprotein particle.        151. The method of any one of paragraphs 148-150, further        comprising the step of introducing into the cell one or more        gRNA and one or more deoxyribonucleic acid (DNA) endonucleases        to effect one or more single-strand breaks (SSBs) or        double-strand breaks (DSBs) within or near a second target gene        that results in a permanent deletion within or near the second        target gene affecting the expression or function of the second        target gene.        152. The method of paragraph 151, wherein the gRNA and        endonuclease form a ribonucleoprotein particle.        153. The method of any one of paragraphs 148-152, wherein the        permanent deletion results in modulating one or more biological        activities.        154. The method of paragraph 153, wherein modulating biological        activities comprises knocking out a biological activity of the        first target gene, the second target gene, optionally a third        target gene, or a combination thereof.        155. The method of paragraph 153 or 154, wherein the biological        activity is host versus graft response, graft versus host        response, immune checkpoint response, immune suppression, or any        combination thereof.        156. The method of paragraph 153 or 154, wherein the biological        activity is a graft versus host response, and the first target        gene, the second target gene, or a combination thereof is        selected from the group consisting of TRAC, CD3-epsilon (CDR),        and combinations thereof.        157. The method of paragraph 153 or 154, wherein the biological        activity is a host versus graft response, and the first target        gene, the second target gene, or a combination thereof is        selected from the group consisting of B2M, CIITA, RFX5, and        combinations thereof.        158. The method of paragraph 153 or 154, wherein the biological        activity is a checkpoint inhibitor, and the first target gene,        the second target gene, or a combination thereof is selected        from the group consisting of PD1, CTLA-4, and combinations        thereof.        159. The method of paragraph 153 or 154, wherein the biological        activity is increased cell survival or enhanced cell viability,        and the first target gene, the second target gene, or a        combination thereof is selected from the group consisting of        TRAC, B2M, PD1, and combinations thereof.        160. The method of paragraph 153 or 154, wherein the gene        encodes a sequence modulating pharmacological control of CAR T.        161. The method of paragraph 160, wherein the gene encodes CD52.        162. The method of paragraph 160, wherein the modulation is        positive or negative.        163. The method of paragraph 160, wherein the modulation allows        the CAR T cells to survive.        164. The method of paragraph 160, wherein the modulation kills        the CAR T cells.        165. The method of any one of paragraphs 153, 154, or 163,        wherein the first target gene, the second target gene, or a        combination thereof comprises a gene selected from the group        consisting of TRAC, CD3ε, B2M, CIITA, RFX5, PD1, CTLA-4, CD52,        PPP1R12C, and combinations thereof.        166. The method of any one of paragraphs 153, 154, or 163,        wherein the first target gene, the second target gene, or a        combination thereof comprises two or more genes selected from        the group consisting of TRAC, B2M, PD1 and combinations thereof.        167. The method of any one of paragraphs 153, 154, or 163,        wherein the first target gene, the second target gene, or a        combination thereof comprises TRAC, B2M and PD1.        168. The method of paragraph 153 or 154, wherein the donor        template is either a single or double stranded polynucleotide.        169. The method of paragraph 168, wherein the portion of the        target gene is selected from the group consisting of TRAC, CD3ε,        B2M, CIITA, RFX5, PD1, CTLA-4, CD52, PPP1R12C, and combinations        thereof.        170. The method of paragraph 169, wherein the portion of the        target gene is selected from the group consisting of TRAC, B2M,        PD1 and combinations thereof.        171. The method of paragraph 169, wherein the portion of the        target gene comprises a portion of TRAC.        172. The method of paragraph 169, wherein the portion of the        target gene comprises a portion of TRAC and/or a portion of B2M.        173. The method of paragraph 169, wherein the portion of the        target gene comprises a portion of TRAC, a portion of B2M,        and/or a portion of PD1.        174. The method of paragraph 153 or 154, wherein the one or more        DNA endonucleases is pre-complexed with one or more gRNAs,        optionally one or more sgRNAs.        175. The method of paragraph 153 or 154, wherein the donor        template is delivered by a viral vector.        176. The method of paragraph 175, wherein the viral vector is an        adeno-associated virus (AAV) vector.        177. The method of paragraph 176, wherein the AAV vector is an        AAV6 vector.        178. The method of paragraph 153 or 154, wherein the cell is a        primary human T cell.        179. The method of paragraph 178, wherein the primary human T        cell is isolated from peripheral blood mononuclear cells        (PBMCs).        180. The method of paragraph 178 or 179, wherein the cells are        allogeneic.        181. The method of any one of paragraphs 148-180, wherein the        one or more DNA endonucleases is a Cas9, or Cpf1 endonuclease;        or a homolog thereof, recombination of the naturally occurring        molecule, codon-optimized, or modified version thereof, and        combinations thereof.        182. The method of paragraph 181, wherein the method comprises        introducing into the cell one or more polynucleotides encoding        the one or more DNA endonucleases.        183. The method of paragraph 182, wherein the method comprises        introducing into the cell one or more ribonucleic acids (RNAs)        encoding the one or more DNA endonucleases.        184. The method of paragraph 181 or 182, wherein the one or more        polynucleotides or one or more RNAs is one or more modified        polynucleotides or one or more modified RNAs.        185. The method of paragraph 184, wherein the DNA endonuclease        is a protein or polypeptide.        186. An ex vivo method for treating a patient with a medical        condition comprising the steps of:    -   i) isolating a T cell from the patient;    -   ii) editing within or near a target gene of the T cell or other        DNA sequences that encode regulatory elements of the target gene        of the T cell; and    -   iii) implanting the genome-edited T cell into the patient.        187. An ex vivo method for treating a patient with a medical        condition comprising the steps of:    -   i) isolating a T cell from a donor;    -   ii) editing within or near a target gene of the T cell or other        DNA sequences that encode regulatory elements of the target gene        of the T cell; and    -   iii) implanting the genome-edited T cell into the patient.        188. The method of paragraph 186 or 187, wherein the isolating        step comprises: cell differential centrifugation, cell        culturing, and combinations thereof.        189. A method for treating a patient with a medical condition        comprising the steps of:    -   i) editing within or near one or more target genes of the T        cell, or one or more other DNA sequences that encode regulatory        elements of the target gene of the T cell; and    -   ii) implanting the genome-edited T cell into the patient.        190. The method of any one of paragraphs 186-189, wherein the        editing step comprises introducing into the T cell (i) the        isolated nucleic acid encoding a knock-in chimeric antigen        receptor (CAR) construct of any one of paragraphs 1-42, (ii) one        or more gRNA and (iii) one or more deoxyribonucleic acid (DNA)        endonucleases to effect one or more single-strand breaks (SSBs)        or double-strand breaks (DSBs) within or near a first target        gene that results in: a) a permanent deletion within or near the        first target gene affecting the expression or function of the        first target gene, optionally wherein the permanent deletion is        in the PAM or sgRNA target sequence, and optionally wherein the        permanent deletion is a 20 nucleotide deletion, b) insertion of        the CAR construct within or near the first target gene, and, c)        expression of the CAR on the surface of a cell.        191. The method of paragraph 190, further comprising the step of        introducing into the cell one or more gRNA and one or more        deoxyribonucleic acid (DNA) endonucleases to effect one or more        single-strand breaks (SSBs) or double-strand breaks (DSBs)        within or near a second target gene that results in a permanent        deletion within or near the second target gene affecting the        expression or function of the second target gene.        192. The method of any one of paragraphs 189-191, wherein the        implanting step comprises implanting the genome-edited T cell        into the patient by transplantation, local injection, or        systemic infusion, or combinations thereof.        193. The method of any one of paragraphs 189-192, wherein the        T-cell is a CD4⁺ T-cell, a CD8⁺ T-cell, or a combination        thereof.        194. The method of any one of paragraphs 189-193, wherein the        medical condition is cancer.        195. The method of paragraph 194, wherein the cancer is B-cell        acute lymphoblastic leukemia (B-ALL), B-cell non-Hodgkin's        lymphoma (B-NHL), Chronic lymphocytic leukemia (C-CLL),        Hodgkin's lymphoma, T cell lymphoma, T cell leukemia, clear cell        renal cell carcinoma (ccRCC), thyroid cancer, nasopharyngeal        cancer, non-small cell lung (NSCLC), pancreatic cancer,        melanoma, ovarian cancer, glioblastoma, cervical cancer, or        multiple myeloma.        196. An in vivo method for treating a patient with a medical        condition comprising the step of editing a first target gene in        a cell of the patient, or other DNA sequences that encode        regulatory elements of the target gene, wherein the editing step        comprises introducing into the T cell (i) the isolated nucleic        acid encoding a knock-in chimeric antigen receptor (CAR)        construct of any one of paragraphs 1-42, (ii) one or more gRNA        and (iii) one or more deoxyribonucleic acid (DNA) endonucleases        to effect one or more single-strand breaks (SSBs) or        double-strand breaks (DSBs) within or near a first target gene        that results in: a) a permanent deletion within or near the        first target gene affecting the expression or function of the        first target gene, optionally wherein the permanent deletion is        in the PAM or sgRNA target sequence, and optionally wherein the        permanent deletion is a 20 nucleotide deletion, b) insertion of        the CAR construct within or near the first target gene, and, c)        expression of the CAR on the surface of the cell.        197. The method of paragraph 196, further comprising the step of        introducing into the cell one or more gRNA and one or more        deoxyribonucleic acid (DNA) endonucleases to effect one or more        single-strand breaks (SSBs) or double-strand breaks (DSBs)        within or near a second target gene that results in a permanent        deletion within or near the second target gene affecting the        expression or function of the second target gene.        198. The method of paragraph 196 or 197, wherein the T-cell is a        CD4⁺ T-cell, a CD8⁺ T-cell, or a combination thereof.        199. The method of any one of paragraphs 196-198, wherein the        medical condition is cancer.        200. The method of paragraph 180, wherein the cancer is B-cell        acute lymphoblastic leukemia (B-ALL), B-cell non-Hodgkin's        lymphoma (B-NHL), Chronic lymphocytic leukemia (C-CLL),        Hodgkin's lymphoma, T cell lymphoma, T cell leukemia, clear cell        renal cell carcinoma (ccRCC), thyroid cancer, nasopharyngeal        cancer, non-small cell lung (NSCLC), pancreatic cancer,        melanoma, ovarian cancer, glioblastoma, cervical cancer, or        multiple myeloma.        201. An isolated nucleic acid comprising a nucleic acid sequence        selected from the group consisting of SEQ ID NOs: 1348-1357.        202. An isolated nucleic acid comprising a nucleic acid sequence        selected from the group consisting of SEQ ID NOs: 1358-1359.        203. An isolated nucleic acid comprising a nucleic acid sequence        selected from the group consisting of SEQ ID NOs: 1361-1364.        204. A method for treating cancer in a subject comprising the        steps of administering to a subject a composition comprising the        isolated cell of any one of paragraphs 101-146.        205. A method for decreasing tumor volume in a subject        comprising the step of administering to a subject a composition        comprising the isolated cell of any one of paragraphs 101-146.        206. A method for increasing survival in a subject with cancer        comprising the step of administering to a subject a composition        comprising the isolated cell of any one of paragraphs 101-146.        207. The composition of any one of paragraphs 60-100, wherein        the isolated nucleic acid comprises a nucleic acid sequence        selected from the group consisting of SEQ ID NOs: 1348-1357,        1358-1359, 1362 and 1364.        208. The composition of any one of paragraphs 60-100 or 207,        wherein the donor template comprises a sequence selected from        the group consisting of SEQ ID Nos: 1390, 1394-1395, 1398 and        1400 and the gRNA is an sgRNA for editing a TRAC gene having the        sequence of SEQ ID NO: 1342.        209. The composition of any one of paragraphs 60-100, 207, or        208, wherein the donor template comprises a sequence selected        from the group consisting of SEQ ID Nos: 1390, 1394-1395, 1398        and 1400, the gRNA is an sgRNA for editing a TRAC gene having        the sequence of SEQ ID NO: 1342 and the sgRNA for editing a B2M        gene having the sequence of SEQ ID NO: 1344.

The term “comprising” or “comprises” is used in reference tocompositions, methods, and respective component(s) thereof, that areessential to the invention, yet open to the inclusion of unspecifiedelements, whether essential or not.

The term “consisting essentially of” refers to those elements requiredfor a given aspect. The term permits the presence of additional elementsthat do not materially affect the basic and novel or functionalcharacteristic(s) of that aspect of the invention.

The term “consisting of” refers to compositions, methods, and respectivecomponents thereof as described herein, which are exclusive of anyelement not recited in that description of the aspect.

The singular forms “a,” “an,” and “the” include plural references,unless the context clearly dictates otherwise.

Certain numerical values presented herein are preceded by the term“about.” The term “about” is used to provide literal support for thenumerical value the term “about” precedes, as well as a numerical valuethat is approximately the numerical value, that is the approximatingunrecited numerical value may be a number which, in the context it ispresented, is the substantial equivalent of the specifically recitednumerical value. The term “about” means numerical values within ±10% ofthe recited numerical value.

When a range of numerical values is presented herein, it is contemplatedthat each intervening value between the lower and upper limit of therange, the values that are the upper and lower limits of the range, andall stated values with the range are encompassed within the disclosure.All the possible sub-ranges within the lower and upper limits of therange are also contemplated by the disclosure.

EXAMPLES

The invention will be more fully understood by reference to thefollowing embodiments, which provide illustrative non-limiting aspectsof the invention.

The examples describe the use of the CRISPR system as an illustrativegenome editing technique to create defined therapeutic genomicdeletions, insertions, or replacements, termed “genomic modifications”herein, in or near a target gene that lead to permanent correction ofmutations in the genomic locus, or expression at a heterologous locus,that restore target protein activity. Introduction of the definedtherapeutic modifications represents a novel therapeutic strategy forthe potential amelioration of various medical conditions, as describedand illustrated herein.

Example 1—Screening of gRNAs

To identify a large spectrum of gRNAs able to edit the cognate DNAtarget region, an in vitro transcribed (IVT) gRNA screen was conducted.Spacer sequences were incorporated into a backbone sequence to generatefull length sgRNAs. Examples of backbone sequences are shown in Table 1.To generate a list of spacer sequences to be used for gene disruption,protein coding exons were selected for each target gene, particularlythose containing the initiating ATG start codon and/or coding forcritical protein domains (e.g., DNA binding domains, extracellulardomains, etc.). The relevant genomic sequence was submitted for analysisusing gRNA design software. The resulting list of gRNAs was narrowed toa list of about ˜200 gRNAs based on uniqueness of sequence (only gRNAswithout a perfect match somewhere else in the genome were screened) andminimal predicted off target effects. This set of gRNAs was in vitrotranscribed, and transfected using messenger Max into HEK293T cells thatconstitutively express Cas9. Cells were harvested 48 hours posttransfection, the genomic DNA was isolated, and editing efficiency wasevaluated using Tracking of Indels by DEcomposition (TIDE) analysis. Theresults are shown in FIGS. 1-5 and Tables below.

It is conventional in the art to describe a gRNA spacer sequence in thecontext of a DNA target (e.g., genomic) sequence, which is adject to thePAM sequence. It is understood, however, that the actual gRNA spacersequence used in the methods and compositions herein is the equivalentof the DNA target sequence. For example, the TRAC gRNA spacer sequencedescribed as including AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 76), actualincludes the RNA spacer sequence AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152).

TRAC gRNA Screen

For TRAC, genomic segments containing the first three (3) protein codingexons were used as input in the gRNA design software. The genomicsegments also included flanking splice site acceptor/donor sequences.Desired gRNAs were those that would lead to insertions or deletions inthe coding sequence disrupting the amino acid sequence of TRAC leadingto out of frame/loss of function allele(s). All 76 in silico-identifiedgRNA spacers targeting TRAC were used in an IVT screen. Seventy three(73) yielded measurable data by TIDE analysis. Nine (9) gRNA sequencesyielded InDel percentages above 50% that could be suitable for secondaryscreens.

A homology-dependent assessment of the TRAC gRNA comprising SEQ ID NO:152 showed that this guide had an indel frequency of less than 0.5% atan off-target site. This data guided selection of this particular TRACgRNA for further analysis.

TABLE 4 TRAC target sequences, gRNA spacer sequences, and cuttingefficiencies in HEK293T cells SEQ ID gRNA Spacer SEQ ID Target SequenceNO: Sequence NO: Guide Name Indel % R² GTAAAACCAA 7 GUAAAACCAA 83 TRAC97.7 0.99 GAGGCCACAG GAGGCCACAG EXON3_T23 GACTGTGCCT 8 GACUGUGCCU 84TRAC 88.4 0.946 CTGTTTGACT CUGUUUGACU EXON3_T15 GTTATGGGCT 9 GUUAUGGGCU85 TRAC 63.5 0.967 TGCATGTCCC UGCAUGUCCC EXON3_T7 TCTCTCAGCT 10UCUCUCAGCU 86 TRAC 59.1 0.949 GGTACACGGC GGUACACGGC EXON1_T1 CACCAAAGCT11 CACCAAAGCU 87 TRAC 59 0.96 GCCCTTACCT GCCCUUACCU EXON1_T15 GAGAATCAAA12 GAGAAUCAAA 88 TRAC 56.5 0.976 ATCGGTGAAT AUCGGUGAAU EXON1_T7ATCCTCCTCCT 13 AUCCUCCUCC 89 TRAC 55.5 0.96 GAAAGTGGC UGAAAGUGGCEXON3_T16 AGCAAGGAAA 14 AGCAAGGAAA 90 TRAC 54.2 0.897 CAGCCTGCGACAGCCUGCGA EXON1_T9 TGTGCTAGAC 15 UGUGCUAGAC 91 TRAC 53.8 0.973ATGAGGTCTA AUGAGGUCUA EXON1_T3 CCGAATCCTC 16 CCGAAUCCUC 92 TRAC 52.10.947 CTCCTGAAAG CUCCUGAAAG EXON3_T13 CCACTTTCAG 17 CCACUUUCAG 93 TRAC46.9 0.955 GAGGAGGATT GAGGAGGAUU EXON3_T19 CATCACAGGA 18 CAUCACAGGA 94TRAC 43.7 0.98 ACTTTCTAAA ACUUUCUAAA EXON2_T8 CGTCATGAGC 19 CGUCAUGAGC95 TRAC 43.5 0.98 AGATTAAACC AGAUUAAACC EXON3_T6 TAGGCAGACA 20UAGGCAGACA 96 TRAC 41.5 0.983 GACTTGTCAC GACUUGUCAC EXON1_T6 ACCCGGCCAC21 ACCCGGCCAC 97 TRAC 40.7 0.975 TTTCAGGAGG UUUCAGGAGG EXON3_T11GCACCAAAGC 22 GCACCAAAGC 98 TRAC 37.6 0.984 TGCCCTTACC UGCCCUUACCEXON1_T5 ACCTGGCCAT 23 ACCUGGCCAU 99 TRAC 37.6 0.79 TCCTGAAGCAUCCUGAAGCA EXON1_T21 TACCAAACCC 24 UACCAAACCC 100 TRAC 37.4 0.939AGTCAAACAG AGUCAAACAG EXON3_T12 GACACCTTCT 25 GACACCUUCU 101 TRAC 37.10.984 TCCCCAGCCC UCCCCAGCCC EXON1_T40 TCTGTTTGACT 26 UCUGUUUGAC 102 TRAC36.6 0.926 GGGTTTGGT UGGGUUUGGU EXON3_T14 TCCTCCTCCTG 27 UCCUCCUCCU 103TRAC 32.8 0.98 AAAGTGGCC GAAAGUGGCC EXON3_T18 AGACTGTGCC 28 AGACUGUGCC104 TRAC 31.4 0.94 TCTGTTTGAC UCUGUUUGAC EXON3_T8 ATGCAAGCCC 29AUGCAAGCCC 105 TRAC 30.7 0.986 ATAACCGCTG AUAACCGCUG EXON3_T1 GCTTTGAAAC30 GCUUUGAAAC 106 TRAC 29.4 0.979 AGGTAAGACA AGGUAAGACA EXON2_T7CAAGAGGCCA 31 CAAGAGGCCA 107 TRAC 28.3 0.987 CAGCGGTTAT CAGCGGUUAUEXON3_T4 CCATAACCGC 32 CCAUAACCGC 108 TRAC 27.5 0.982 TGTGGCCTCTUGUGGCCUCU EXON3_T9 ACAAAACTGT 33 ACAAAACUGU 109 TRAC 27.4 0.988GCTAGACATG GCUAGACAUG EXON1_T16 TTCGGAACCC 34 UUCGGAACCC 110 TRAC 26.90.984 AATCACTGAC AAUCACUGAC EXON3_T5 GATTAAACCC 35 GAUUAAACCC 111 TRAC26.6 0.984 GGCCACTTTC GGCCACUUUC EXON3_T2 TCTGTGGGAC 36 UCUGUGGGAC 112TRAC 24.4 0.989 AAGAGGATCA AAGAGGAUCA EXON1_T20 GCTGGTACAC 37 GCUGGUACAC113 TRAC 24.1 0.991 GGCAGGGTCA GGCAGGGUCA EXON1_T22 CTCTCAGCTG 38CUCUCAGCUG 114 TRAC 23.7 0.99 GTACACGGCA GUACACGGCA EXON1_T13 CTGACAGGTT39 CUGACAGGUU 115 TRAC 23.3 0.982 TTGAAAGTTT UUGAAAGUUU EXON3_T25AGAGTCTCTC 40 AGAGUCUCUC 116 TRAC 18.9 0.992 AGCTGGTACA AGCUGGUACAEXON1_T25 CTCGACCAGC 41 CUCGACCAGC 117 TRAC 16.5 0.992 TTGACATCACUUGACAUCAC EXON2_T1 TAAACCCGGC 42 UAAACCCGGC 118 TRAC 12.9 0.991CACTTTCAGG CACUUUCAGG EXON3_T10 GTCAGGGTTC 43 GUCAGGGUUC 119 TRAC 12.80.992 TGGATATCTG UGGAUAUCUG EXON1_T27 TTCGTATCTGT 44 UUCGUAUCUG 120 TRAC12.8 0.994 AAAACCAAG UAAAACCAAG EXON3_T24 CTTCAAGAGC 45 CUUCAAGAGC 121TRAC 12.5 0.99 AACAGTGCTG AACAGUGCUG EXON1_T17 CTGGATATCT 46 CUGGAUAUCU122 TRAC 12.1 0.992 GTGGGACAAG GUGGGACAAG EXON1_T31 AAGTTCCTGT 47AAGUUCCUGU 123 TRAC 11.6 0.991 GATGTCAAGC GAUGUCAAGC EXON2_T3 GGCAGCTTTG48 GGCAGCUUUG 124 TRAC 11 0.99 GTGCCTTCGC GUGCCUUCGC EXON1_T2CTTCTTCCCCA 49 CUUCUUCCCC 125 TRAC 10.6 0.993 GCCCAGGTA AGCCCAGGUAEXON1_T33 TTCAAAACCT 50 UUCAAAACCU 126 TRAC 9.4 0.966 GTCAGTGATTGUCAGUGAUU EXON3_T21 TCAGGGTTCT 51 UCAGGGUUCU 127 TRAC 9.3 0.973GGATATCTGT GGAUAUCUGU EXON1_T18 GTCGAGAAAA 52 GUCGAGAAAA 128 TRAC 8.90.991 GCTTTGAAAC GCUUUGAAAC EXON2_T4 TTAATCTGCTC 53 UUAAUCUGCU 129 TRAC8.7 0.993 ATGACGCTG CAUGACGCUG EXON3_T26 CTGTTTCCTTG 54 CUGUUUCCUU 130TRAC 7.6 0.99 CTTCAGGAA GCUUCAGGAA EXON1_T39 TGGATTTAGA 55 UGGAUUUAGA131 TRAC 7.3 0.993 GTCTCTCAGC GUCUCUCAGC EXON1_T4 CTTACCTGGG 56CUUACCUGGG 132 TRAC 6.7 0.993 CTGGGGAAGA CUGGGGAAGA EXON1_T38 AGCCCAGGTA57 AGCCCAGGUA 133 TRAC 6.1 0.994 AGGGCAGCTT AGGGCAGCUU EXON1_T11GGGACAAGAG 58 GGGACAAGAG 134 TRAC 5 0.993 GATCAGGGTT GAUCAGGGUUEXON1_T26 TTCTTCCCCAG 59 UUCUUCCCCA 135 TRAC 4.9 0.994 CCCAGGTAAGCCCAGGUAA EXON1_T35 TGCCTCTGTTT 60 UGCCUCUGUU 136 TRAC 4.9 0.94GACTGGGTT UGACUGGGUU EXON3_T17 AGCTGGTACA 61 AGCUGGUACA 137 TRAC 4.30.994 CGGCAGGGTC CGGCAGGGUC EXON1_T8 TGCTCATGAC 62 UGCUCAUGAC 138 TRAC3.4 0.994 GCTGCGGCTG GCUGCGGCUG EXON3_T27 TTTCAAAACC 63 UUUCAAAACC 139TRAC 2.1 0.965 TGTCAGTGAT UGUCAGUGAU EXON3_T20 ACACGGCAGG 64 ACACGGCAGG140 TRAC 1.4 0.994 GTCAGGGTTC GUCAGGGUUC EXON1_T14 AGCTTTGAAA 65AGCUUUGAAA 141 TRAC 1.4 0.993 CAGGTAAGAC CAGGUAAGAC EXON2_T5 CTGGGGAAGA66 CUGGGGAAGA 142 TRAC 1.3 0.994 AGGTGTCTTC AGGUGUCUUC EXON1_T28TCCTTGCTTCA 67 UCCUUGCUUC 143 TRAC 1.2 0.98 GGAATGGCC AGGAAUGGCCEXON1_T29 AAGCTGCCCT 68 AAGCUGCCCU 144 TRAC 1.1 0.995 TACCTGGGCTUACCUGGGCU EXON1_T24 AACAAATGTG 69 AACAAAUGUG 145 TRAC 1.1 0.995TCACAAAGTA UCACAAAGUA EXON1_T36 AAAGTCAGAT 70 AAAGUCAGAU 146 TRAC 0.80.995 TTGTTGCTCC UUGUUGCUCC EXON1_T12 AGCTGCCCTT 71 AGCUGCCCUU 147 TRAC0.8 0.995 ACCTGGGCTG ACCUGGGCUG EXON1_T30 TGGAATAATG 72 UGGAAUAAUG 148TRAC 0.8 0.994 CTGTTGTTGA CUGUUGUUGA EXON1_T34 ATTTGTTTGA 73 AUUUGUUUGA149 TRAC 0.7 0.996 GAATCAAAAT GAAUCAAAAU EXON1_T37 AAAGCTGCCC 74AAAGCUGCCC 150 TRAC 0.5 0.995 TTACCTGGGC UUACCUGGGC EXON1_T10 CCAAGAGGCC75 CCAAGAGGCC 151 TRAC 0.5 0.994 ACAGCGGTTA ACAGCGGUUA EXON3_T3AGAGCAACAG 76 AGAGCAACAG 152 TRAC 0.2 0.994 TGCTGTGGCC UGCUGUGGCCEXON1_T32 ATCTGTGGGA 77 AUCUGUGGGA 153 TRAC 0.1 0.994 CAAGAGGATCCAAGAGGAUC EXON1_T19 GGTAAGACAG 78 GGUAAGACAG 154 TRAC 0.1 0.993GGGTCTAGCC GGGUCUAGCC EXON2_T2 GTAAGACAGG 79 GUAAGACAGG 155 TRAC 0.10.994 GGTCTAGCCT GGUCUAGCCU EXON2_T6 GCAGGCTGTT 80 GCAGGCUGUU 156 TRACTCCTTGCTTC UCCUUGCUUC EXON1_T23 CTTTGAAACA 81 CUUUGAAACA 157 TRACGGTAAGACAG GGUAAGACAG EXON2_T9 AGAGGCACAG 82 AGAGGCACAG 158 TRACTCTCTTCAGC UCUCUUCAGC EXON3_T22

In some embodiments, a gRNA comprises the sequence of any one of SEQ IDNOs: 83-158 or targets the sequence of any one of SEQ ID NOs: 7-82.

CDR gRNA Screen

For CD3ε (CD3E), genomic segments containing the five (5) protein codingexons were used as input in the gRNA design software. The genomicsegments also included flanking splice site acceptor/donor sequences.Desired gRNAs were those that would lead to insertions or deletions inthe coding sequence disrupting the amino acid sequence of CD3E leadingto out of frame/loss of function allele(s). One hundred twenty five(125) in silico identified gRNA spacers targeting CD3E were used in anIVT screen. One hundred twenty (120) yielded measurable data by TIDEanalysis. Nine (9) gRNA sequences yielded InDel percentages above 50%that could be suitable for secondary screens.

TABLE 5CD3E target sequences, gRNA spacer sequences, and cutting efficienciesin HEK293T cells SEQ ID gRNA Spacer SEQ ID Target Sequence NO: sequenceNO: Guide Name Indel % R² GTCAGAGGAG 159 GUCAGAGGAG 284 CD3E 83.2 0.976ATTCCTGCCA AUUCCUGCCA exon4_T18 AGAGGAGATT 160 AGAGGAGAUU 285 CD3E 61.60.955 CCTGCCAAGG CCUGCCAAGG exon4_T20 GAACTTTTATC 161 GAACUUUUAU 286CD3E 58.8 0.984 TCTACCTGA CUCUACCUGA exon3_T22 AAGCCTGTGA 162 AAGCCUGUGA287 CD3E 57.8 0.919 CACGAGGAGC CACGAGGAGC exon4_T11 CATCCTACTCA 163CAUCCUACUC 288 CD3E 54.9 0.978 CCTGATAAG ACCUGAUAAG exon1_T14CTGGATTACCT 164 CUGGAUUACC 289 CD3E 54.4 0.98 CTTGCCCTC UCUUGCCCUCexon3_T12 CATGAAACAA 165 CAUGAAACAA 290 CD3E 53.1 0.97 AGATGCAGTCAGAUGCAGUC exon1_T18 ATTTCAGATCC 166 AUUUCAGAUC 291 CD3E 51.5 0.964AGGATACTG CAGGAUACUG exon3_T13 TCAGAGGAGA 167 UCAGAGGAGA 292 CD3E 51.30.96 TTCCTGCCAA UUCCUGCCAA exon4_T12 GCAGTTCTCAC 168 GCAGUUCUCA 293 CD3E49.6 0.975 ACACTGTGG CACACUGUGG exon4_T29 CACAATGATA 169 CACAAUGAUA 294CD3E 49.1 0.95 AAAACATAGG AAAACAUAGG exon3_T28 GTGTGAGAAC 170 GUGUGAGAAC295 CD3E 48.8 0.84 TGCATGGAGA UGCAUGGAGA exon4_T37 GATGTCCACTA 171GAUGUCCACU 296 CD3E 48 0.93 TGACAATTG AUGACAAUUG exon4_T4 ACTCACCTGAT172 ACUCACCUGA 297 CD3E 45.5 0.959 AAGAGGCAG UAAGAGGCAG exon1_T13CTCTTATCAGG 173 CUCUUAUCAG 298 CD3E 44.1 0.974 TGAGTAGGA GUGAGUAGGAexon1_T7 TATCTCTACCT 174 UAUCUCUACC 299 CD3E 43.6 0.764 GAGGGCAAGUGAGGGCAAG exon3_T10 ATCCTGGATCT 175 AUCCUGGAUC 300 CD3E 43.5 0.951GAAATACTA UGAAAUACUA exon3_T20 AGATGGAGAC 176 AGAUGGAGAC 301 CD3E 42.40.955 TTTATATGCT UUUAUAUGCU exon3_T14 CTGCCTCTTAT 177 CUGCCUCUUA 302CD3E 40.1 0.967 CAGGTGAGT UCAGGUGAGU exon1_T5 TATATGCTGGG 178 UAUAUGCUGG303 CD3E 40 0.972 GAGAAAGAA GGAGAAAGAA exon3_T29 AGTGGACATC 179AGUGGACAUC 304 CD3E 38.8 0.969 TGCATCACTG UGCAUCACUG exon4_T24CAAGCCTGTG 180 CAAGCCUGUG 305 CD3E 38 0.974 ACACGAGGAG ACACGAGGAGexon4_T10 GTGGACATCT 181 GUGGACAUCU 306 CD3E 36.9 0.947 GCATCACTGGGCAUCACUGG exon4_T13 GATGGAGACT 182 GAUGGAGACU 307 CD3E 36.1 0.973TTATATGCTG UUAUAUGCUG exon3_T5 TCTCACACACT 183 UCUCACACAC 308 CD3E 35.80.924 GTGGGGGGT UGUGGGGGGU exon4_T21 CAGGCAAAGG 184 CAGGCAAAGG 309 CD3EGGTAAGGCTG GGUAAGGCUG exon4_T38 35.2 0.817 GTTACCTCATA 185 GUUACCUCAU310 CD3E 35.1 0.978 GTCTGGGTT AGUCUGGGUU exon5_T7 CTTCTGGTTTG 186CUUCUGGUUU 311 CD3E 34.2 0.985 CTTCCTCTG GCUUCCUCUG exon3_T33ATGCAGTTCTC 187 AUGCAGUUCU 312 CD3E 32.3 0.967 ACACACTGT CACACACUGUexon4_T30 CCCACGTTACC 188 CCCACGUUAC 313 CD3E 30.4 0.977 TCATAGTCTCUCAUAGUCU exon5_T5 TTCCTCCGCAG 189 UUCCUCCGCA 314 CD3E 30.2 0.979GACAAAACA GGACAAAACA exon5_T11 CTGGGCCTCTG 190 CUGGGCCUCU 315 CD3E 30.10.987 CCTCTTATC GCCUCUUAUC exon1_T12 GGAGATGGAT 191 GGAGAUGGAU 316 CD3E30.1 0.98 GTGATGTCGG GUGAUGUCGG exon4_T14 TGTTCCCAACC 192 UGUUCCCAAC 317CD3E 29.9 0.977 CAGACTATG CCAGACUAUG exon5_T10 ACACGAGGAG 193 ACACGAGGAG318 CD3E 28.8 0.982 CGGGTGCTGG CGGGUGCUGG exon4_T25 TTATATGCTGG 194UUAUAUGCUG 319 CD3E 28.3 0.98 GGAGAAAGA GGGAGAAAGA exon3_T30 TTTCAGATCCA195 UUUCAGAUCC 320 CD3E 28 0.771 GGATACTGA AGGAUACUGA exon3_T17CATGGAGATG 196 CAUGGAGAUG 321 CD3E 28 0.97 GATGTGATGT GAUGUGAUGUexon4_T32 AGATGCAGTC 197 AGAUGCAGUC 322 CD3E 27.5 0.982 GGGCACTCACGGGCACUCAC exon1_T1 TATTATGTCTG 198 UAUUAUGUCU 323 CD3E 27.5 0.988CTACCCCAG GCUACCCCAG exon3_T11 GTTTCCCCTCC 199 GUUUCCCCUC 324 CD3E 27.10.984 TTCCTCCGC CUUCCUCCGC exon5_T18 TAAAAACATA 200 UAAAAACAUA 325 CD3E26.5 0.895 GGCAGTGATG GGCAGUGAUG exon3_T25 GGTGGCCACA 201 GGUGGCCACA 326CD3E 26.1 0.986 ATTGTCATAG AUUGUCAUAG exon4_T2 GCATATAAAG 202 GCAUAUAAAG327 CD3E 25 0.98 TCTCCATCTC UCUCCAUCUC exon3_T16 TATTACTGTGG 203UAUUACUGUG 328 CD3E 25 0.984 TTCCAGAGA GUUCCAGAGA exon3_T21 CAACACAATG204 CAACACAAUG 329 CD3E 24.6 0.963 ATAAAAACAT AUAAAAACAU exon3_T26GTAATCCAGG 205 GUAAUCCAGG 330 CD3E 24.2 0.991 TCTCCAGAAC UCUCCAGAACexon3_T7 CCCAGACTAT 206 CCCAGACUAU 331 CD3E 24.1 0.979 GAGGTAACGTGAGGUAACGU exon5_T1 ATAGTGGACA 207 AUAGUGGACA 332 CD3E 24 0.96TCTGCATCAC UCUGCAUCAC exon4_T8 ATCTTCTGGTT 208 AUCUUCUGGU 333 CD3E 23.90.981 TGCTTCCTC UUGCUUCCUC exon3_T19 TTTTGTCCTGC 209 UUUUGUCCUG 334 CD3E23.7 0.963 GGAGGAAGG CGGAGGAAGG exon5_T15 CTGAGGGCAA 210 CUGAGGGCAA 335CD3E 22.5 0.989 GAGGTAATCC GAGGUAAUCC exon3_T8 TTGACATGCCC 211UUGACAUGCC 336 CD3E 22.4 0.978 TCAGTATCC CUCAGUAUCC exon3_T4 CAGAGGAGAT212 CAGAGGAGAU 337 CD3E 21.8 0.989 TCCTGCCAAG UCCUGCCAAG exon4_T17TGCTGCTGCTG 213 UGCUGCUGCU 338 CD3E 20.8 0.987 GTTTACTAC GGUUUACUACexon4_T3 GAGGTAACGT 214 GAGGUAACGU 339 CD3E 20.5 0.965 GGGATAGAAAGGGAUAGAAA exon5_T20 ACCCAGACTA 215 ACCCAGACUA 340 CD3E 20.3 0.977TGAGGTAACG UGAGGUAACG exon5_T2 CACTGGGGGC 216 CACUGGGGGC 341 CD3E 200.987 TTGCTGCTGC UUGCUGCUGC exon4_T26 ATCAGGTGAG 217 AUCAGGUGAG 342 CD3E19.9 0.989 TAGGATGGAG UAGGAUGGAG exon1_T15 GGCACTCACT 218 GGCACUCACU 343CD3E 19 0.988 GGAGAGTTCT GGAGAGUUCU exon1_T17 TTTGTCCTGCG 219 UUUGUCCUGC344 CD3E 18.7 0.977 GAGGAAGGA GGAGGAAGGA exon5_T16 TGAGGATCAC 220UGAGGAUCAC 345 CD3E 18.2 0.771 CTGTCACTGA CUGUCACUGA exon3_T15TTACTTTACTA 221 UUACUUUACU 346 CD3E 18 0.987 AGATGGCGG AAGAUGGCGGexon1_T2 TAAAAACATA 222 UAAAAACAUA 347 CD3E 17 0.971 GGCGGTGATGGGCGGUGAUG exon3_T1 CTGAAAATTCC 223 CUGAAAAUUC 348 CD3E 16.9 0.779TTCAGTGAC CUUCAGUGAC exon3_T18 TTGTCCTGCGG 224 UUGUCCUGCG 349 CD3E 16.90.99 AGGAAGGAG GAGGAAGGAG exon5_T21 TCTTCTGGTTT 225 UCUUCUGGUU 350 CD3E16.5 0.98 GCTTCCTCT UGCUUCCUCU exon3_T31 GGGCACTCAC 226 GGGCACUCAC 351CD3E 15.7 0.989 TGGAGAGTTC UGGAGAGUUC exon1_T8 TTCTCACACAC 227UUCUCACACA 352 CD3E 15.4 0.967 TGTGGGGGG CUGUGGGGGG exon4_T31 CGGGTGCTGG228 CGGGUGCUGG 353 CD3E 14.8 0.986 CGGCAGGCAA CGGCAGGCAA exon4_T19AGGTAACGTG 229 AGGUAACGUG 354 CD3E 14.7 0.982 GGATAGAAAT GGAUAGAAAUexon5_T12 CTGTTACTTTA 230 CUGUUACUUU 355 CD3E 14.6 0.986 CTAAGATGGACUAAGAUGG exon1_T9 CCTCTCCTTGT 231 CCUCUCCUUG 356 CD3E 13.7 0.984TTTGTCCTG UUUUGUCCUG exon5_T17 TAGTGGACAT 232 UAGUGGACAU 357 CD3E 13.50.978 CTGCATCACT CUGCAUCACU exon4_T15 GGACTGTTACT 233 GGACUGUUAC 358CD3E 12.2 0.99 TTACTAAGA UUUACUAAGA exon1_T6 ACTGAAGGAA 234 ACUGAAGGAA359 CD3E 11.9 0.966 TTTTCAGAAT UUUUCAGAAU exon3_T27 CCATGAAACA 235CCAUGAAACA 360 CD3E 11.5 0.987 AAGATGCAGT AAGAUGCAGU exon1_T16GAGATGGAGA 236 GAGAUGGAGA 361 CD3E 11.3 0.986 CTTTATATGC CUUUAUAUGCexon3_T2 TTTTCAGAATT 237 UUUUCAGAAU 362 CD3E 11 0.993 GGAGCAAAGUGGAGCAAAG exon3_T23 TCATAGTCTGG 238 UCAUAGUCUG 363 CD3E 10.5 0.984GTTGGGAAC GGUUGGGAAC exon5_T14 CCGCAGGACA 239 CCGCAGGACA 364 CD3E 10.30.985 AAACAAGGAG AAACAAGGAG exon5_T13 TCTGGGTTGGG 240 UCUGGGUUGG 365CD3E 9.5 0.991 AACAGGTGG GAACAGGUGG exon5_T22 ACACAGACAC 241 ACACAGACAC366 CD3E 9.1 0.926 GTGAGTTTAT GUGAGUUUAU exon2_T1 GCCAGCAGAC 242GCCAGCAGAC 367 CD3E 9 0.987 TTACTACTTC UUACUACUUC exon1_T3 TAGTCTGGGTT243 UAGUCUGGGU 368 CD3E 9 0.99 GGGAACAGG UGGGAACAGG exon5_T19CGAACTTTTAT 244 CGAACUUUUA 369 CD3E 8.7 0.983 CTCTACCTG UCUCUACCUGexon3_T24 CGCTCCTCGTG 245 CGCUCCUCGU 370 CD3E 8 0.987 TCACAGGCTGUCACAGGCU exon4_T9 CTACTGGAGC 246 CUACUGGAGC 371 CD3E 8 0.972AAGAATAGAA AAGAAUAGAA exon4_T28 CGTTACCTCAT 247 CGUUACCUCA 372 CD3E 7.90.984 AGTCTGGGT UAGUCUGGGU exon5_T4 AGATAAAAGT 248 AGAUAAAAGU 373 CD3E7.8 0.969 TCGCATCTTC UCGCAUCUUC exon3_T3 AAGGCCAAGC 249 AAGGCCAAGC 374CD3E 7.8 0.989 CTGTGACACG CUGUGACACG exon4_T5 TGGCGGCAGG 250 UGGCGGCAGG375 CD3E 7.7 0.985 CAAAGGGGTA CAAAGGGGUA exon4_T34 AGGGCATGTC 251AGGGCAUGUC 376 CD3E 7.4 0.925 AATATTACTG AAUAUUACUG exon3_T6 TCGTGTCACAG252 UCGUGUCACA 377 CD3E 7.4 0.98 GCTTGGCCT GGCUUGGCCU exon4_T16TGCAGTTCTCA 253 UGCAGUUCUC 378 CD3E 7.3 0.973 CACACTGTG ACACACUGUGexon4_T23 GGGGGGTGGG 254 GGGGGGUGGG 379 CD3E 7 0.975 GTGGGGAGAGGUGGGGAGAG exon4_T41 GATGAGGATG 255 GAUGAGGAUG 380 CD3E 6.7 0.991ATAAAAACAT AUAAAAACAU exon3_T32 CATGCAGTTCT 256 CAUGCAGUUC 381 CD3E 6.40.987 CACACACTG UCACACACUG exon4_T35 ACGTGGGATA 257 ACGUGGGAUA 382 CD3E6.3 0.987 GAAATGGGCC GAAAUGGGCC exon5_T9 TACCACCTGA 258 UACCACCUGA 383CD3E 5.3 0.94 AAATGAAAAA AAAUGAAAAA exon2_T4 TGGCAGGAAT 259 UGGCAGGAAU384 CD3E 5 0.989 CTCCTCTGAC CUCCUCUGAC exon4_T7 CTCACACACTG 260CUCACACACU 385 CD3E 5 0.975 TGGGGGGTG GUGGGGGGUG exon4_T33 GTGACACGAG261 GUGACACGAG 386 CD3E 4.9 0.988 GAGCGGGTGC GAGCGGGUGC exon4_T6CAGTTCTCACA 262 CAGUUCUCAC 387 CD3E 4.9 0.971 CACTGTGGG ACACUGUGGGexon4_T40 TGCCATAGTAT 263 UGCCAUAGUA 388 CD3E 4.6 0.984 TTCAGATCCUUUCAGAUCC exon3_T9 TCCAGAAGTA 264 UCCAGAAGUA 389 CD3E 4.3 0.989GTAAGTCTGC GUAAGUCUGC exon1_T4 GGTGCTGGCG 265 GGUGCUGGCG 390 CD3E 4.30.971 GCAGGCAAAG GCAGGCAAAG exon4_T36 TCCCACGTTAC 266 UCCCACGUUA 391CD3E 4.3 0.992 CTCATAGTC CCUCAUAGUC exon5_T3 CACAGTGTGT 267 CACAGUGUGU392 CD3E 3.9 0.986 GAGAACTGCA GAGAACUGCA exon4_T27 CGACTGCATCT 268CGACUGCAUC 393 CD3E 3.8 0.989 TTGTTTCAT UUUGUUUCAU exon1_T11 GGGTGCTGGC269 GGGUGCUGGC 394 CD3E 3.8 0.994 GGCAGGCAAA GGCAGGCAAA exon4_T42GAGGAGCGGG 270 GAGGAGCGGG 395 CD3E 3.3 0.994 TGCTGGCGGC UGCUGGCGGCexon4_T45 TTGTTTTGTCC 271 UUGUUUUGUC 396 CD3E 3.2 0.99 TGCGGAGGACUGCGGAGGA exon5_T8 CTCCTTGTTTT 272 CUCCUUGUUU 397 CD3E 3.1 0.99GTCCTGCGG UGUCCUGCGG exon5_T6 CCGACTGCATC 273 CCGACUGCAU 398 CD3E 1.90.991 TTTGTTTCA CUUUGUUUCA exon1_T10 TGTTTCCTTTT 274 UGUUUCCUUU 399 CD3E1.9 0.92 TTCATTTTC UUUCAUUUUC exon2_T2 TTCCTTTTTTC 275 UUCCUUUUUU 400CD3E 1.5 0.94 ATTTTCAGG CAUUUUCAGG exon2_T3 AGGCTGTGGA 276 AGGCUGUGGA401 CD3E 1.2 0.992 GTCCAGTCAG GUCCAGUCAG exon4_T22 TGGGGGGTGG 277UGGGGGGUGG 402 CD3E 0.9 0.991 GGTGGGGAGA GGUGGGGAGA exon4_T44 ACACTGTGGG278 ACACUGUGGG 403 CD3E 0.3 0.992 GGGTGGGGTG GGGUGGGGUG exon4_T47CACACTGTGG 279 CACACUGUGG 404 CD3E 0.2 0.992 GGGGTGGGGT GGGGUGGGGUexon4_T43 GTGGGGGGTG 280 GUGGGGGGUG 405 CD3E 0 0.993 GGGTGGGGAGGGGUGGGGAG exon4_T46 ACACACTGTG 281 ACACACUGUG 406 CD3E 0 0.992GGGGGTGGGG GGGGGUGGGG exon4_T48 GCACCCGCTCC 282 GCACCCGCUC 407 CD3ETCGTGTCAC CUCGUGUCAC exon4_T1 GAGCAAGAAT 283 GAGCAAGAAU 408 CD3EAGAAAGGCCA AGAAAGGCCA exon4_T39

In some embodiments, a gRNA comprises the sequence of any one of SEQ IDNOs: 284-408 or targets the sequence of any one of SEQ ID NOs: 159-283.

B2M gRNA Screen

For B2M, genomic segments containing the first three (3) protein codingexons were used as input in the gRNA design software. The genomicsegments also included flanking splice site acceptor/donor sequences.Desired gRNAs were those that would lead to insertions or deletions inthe coding sequence disrupting the amino acid sequence of B2M leading toout of frame/loss of function allele(s). All forty nine (49) insilico-identified gRNA spacers targeting B2M were used in an IVT screen.All gRNAs yielded measurable data by TIDE analysis. Eight (8) gRNAsequences yielded InDel percentages above 50% that could be suitable forsecondary screens.

A homology-dependent assessment of the B2M gRNA comprising SEQ ID NO:466 showed that this guide had an indel frequency of less than 0.5% atan off-target site. This data guided selection of this particular B2MgRNA for further analysis.

TABLE 6B2M target sequences, gRNA spacer sequences, and cutting efficienciesin HEK293T cells SEQ ID SEQ ID Target Sequence NO: gRNA Spacer NO:Guide Name Indel % R² TCCTGAAGCTG 409 UCCUGAAGCU 458 B2M 89.5 0.924ACAGCATTC GACAGCAUUC EXON1_T13 CAGTAAGTCAA 410 CAGUAAGUC 459 B2M 80.40.966 CTTCAATGT AACUUCAAU EXON2_T9 GU GGCCGAGATGT 411 GGCCGAGAU 460 B2M70.7 0.99 CTCGCTCCG GUCUCGCUCC EXON1_T2 G ACAAAGTCACA 412 ACAAAGUCAC 461B2M 65.5 0.972 TGGTTCACA AUGGUUCAC EXON2_T23 A CGCGAGCACA 413 CGCGAGCACA462 B2M 60.3 0.972 GCTAAGGCCA GCUAAGGCCA EXON1_T11 CATACTCATCT 414CAUACUCAUC 463 B2M 59.9 0.989 TTTTCAGTG UUUUUCAGU EXON2_T24 GACTCTCTCTTT 415 ACUCUCUCUU 464 B2M 57.1 0.96 CTGGCCTGG UCUGGCCUGGEXON1_T19 CTCGCGCTACT 416 CUCGCGCUAC 465 B2M 54.8 0.812 CTCTCTTTCUCUCUCUUUC EXON1_T12 GCTACTCTCTC 417 GCUACUCUCU 466 B2M 45.9 0.867TTTCTGGCC CUUUCUGGCC EXON1_T20 TCTCTCCTACC 418 UCUCUCCUAC 467 B2M 43.50.968 CTCCCGCTC CCUCCCGCUC EXON1_T15 CAGCCCAAGAT 419 CAGCCCAAGA B2M 42.70.988 AGTTAAGTG UAGUUAAGU 468 EXON2_T5 G TCACGTCATCC 420 UCACGUCAUC 469B2M 39.8 0.974 AGCAGAGAA CAGCAGAGA EXON2_T17 A TTACCCCACTT 421UUACCCCACU 470 B2M 32.7 0.977 AACTATCTT UAACUAUCU EXON2_T11 U GGCCACGGAG422 GGCCACGGAG 471 B2M 32.1 0.99 CGAGACATCT CGAGACAUCU EXON1_T8CTTACCCCACT 423 CUUACCCCAC 472 B2M 31.9 0.984 TAACTATCT UUAACUAUCEXON2_T7 U GGCATACTCAT 424 GGCAUACUCA 473 B2M 31.7 0.985 CTTTTTCAGUCUUUUUCA EXON2_T15 G TATAAGTGGAG 425 UAUAAGUGG 474 B2M 31.6 0.991GCGTCGCGC AGGCGUCGCG EXON1_T1 C GCCCGAATGCT 426 GCCCGAAUGC 475 B2M 30.50.99 GTCAGCTTC UGUCAGCUUC EXON1_T10 GAAGTTGACTT 427 GAAGUUGAC 476 B2M30.4 0.98 ACTGAAGAA UUACUGAAG EXON2_T19 AA GAGGAAGGAC 428 GAGGAAGGA 477B2M 28.9 0.993 CAGAGCGGGA CCAGAGCGGG EXON1_T18 A AAGTGGAGGC 429AAGUGGAGG 478 B2M 27.1 0.983 GTCGCGCTGG CGUCGCGCUG EXON1_T4 GACTCACGCTGG 430 ACUCACGCUG 479 B2M 22.3 0.992 ATAGCCTCC GAUAGCCUCCEXON1_T7 GAGTAGCGCG 431 GAGUAGCGC 480 B2M 20.8 0.97 AGCACAGCTAGAGCACAGCU EXON1_T5 A AGGGTAGGAG 432 AGGGUAGGA 481 B2M 19.9 0.993AGACTCACGC GAGACUCACG EXON1_T9 C TTCAGACTTGT 433 UUCAGACUU 482 B2M 18.90.991 CTTTCAGCA GUCUUUCAGC EXON2_T21 A CACAGCCCAAG 434 CACAGCCCAA 483B2M 18.6 0.991 ATAGTTAAG GAUAGUUAA EXON2_T6 G TTGGAGTACCT 435 UUGGAGUAC484 B2M 18.1 0.99 GAGGAATAT CUGAGGAAU EXON2_T26 AU AAGGACCAGA 436AAGGACCAG 485 B2M 17.4 0.994 GCGGGAGGGT AGCGGGAGG EXON1_T16 GUAGAGGAAGGA 437 AGAGGAAGG 486 B2M 17.4 0.992 CCAGAGCGGG ACCAGAGCGGEXON1_T17 G AAGTCAACTTC 438 AAGUCAACU 487 B2M 15.2 0.981 AATGTCGGAUCAAUGUCG EXON2_T2 GA AGTGGAGGCGT 439 AGUGGAGGC 488 B2M 14.2 0.995CGCGCTGGC GUCGCGCUGG EXON1_T3 C TGGAGTACCTG 440 UGGAGUACC 489 B2M 11.70.98 AGGAATATC UGAGGAAUA EXON2_T12 UC ACAGCCCAAG 441 ACAGCCCAAG 490 B2M11.5 0.995 ATAGTTAAGT AUAGUUAAG EXON2_T4 U CGTGAGTAAAC 442 CGUGAGUAA 491B2M 10.4 0.99 CTGAATCTT ACCUGAAUCU EXON2_T3 U TGGAGAGAGA 443 UGGAGAGAG492 B2M 9.2 0.993 ATTGAAAAAG AAUUGAAAA EXON2_T28 AG ATACTCATCTT 444AUACUCAUCU 493 B2M 8 0.988 TTTCAGTGG UUUUCAGUG EXON2_T25 G AGTCACATGGT445 AGUCACAUG 494 B2M 6.4 0.99 TCACACGGC GUUCACACGG EXON2_T1 CCACGCGTTTAA 446 CACGCGUUUA 495 B2M 5.2 0.99 TATAAGTGG AUAUAAGUG EXON1_T6G CTCAGGTACTC 447 CUCAGGUACU 496 B2M 5 0.99 CAAAGATTC CCAAAGAUUCEXON2_T8 TTTGACTTTCC 448 UUUGACUUU 497 B2M 4.8 0.991 ATTCTCTGCCCAUUCUCUG EXON2_T27 C ACCCAGACACA 449 ACCCAGACAC 498 B2M 4.7 0.992TAGCAATTC AUAGCAAUU EXON2_T13 C TGGGCTGTGAC 450 UGGGCUGUG 499 B2M 4.40.993 AAAGTCACA ACAAAGUCAC EXON2_T22 A CTGAATCTTTG 451 CUGAAUCUU 500 B2M3 0.993 GAGTACCTG UGGAGUACC EXON2_T14 UG TTCCTGAATTG 452 UUCCUGAAU 501B2M 3 0.992 CTATGTGTC UGCUAUGUG EXON2_T16 UC ACTTGTCTTTC 453 ACUUGUCUU502 B2M 2.8 0.992 AGCAAGGAC UCAGCAAGG EXON2_T10 AC TTCCTGAAGCT 454UUCCUGAAGC 503 B2M 2.5 0.994 GACAGCATT UGACAGCAU EXON1_T14 U GCATACTCATC455 GCAUACUCAU 504 B2M 2.4 0.988 TTTTTCAGT CUUUUUCAG EXON2_T20 UTCCTGAATTGC 456 UCCUGAAUU 505 B2M 1.9 0.99 TATGTGTCT GCUAUGUGU EXON2_T18CU TCATAGATCGA 457 UCAUAGAUC 506 B2M 1.5 0.992 GACATGTAA GAGACAUGUEXON3_T1 AA

In some embodiments, a gRNA comprises the sequence of any one of SEQ IDNOs: 458-506 or targets the sequence of any one of SEQ ID NOs: 409-457.

CIITA gRNA Screen

For CIITA, genomic segments containing the ATG exon downstream of theType 3 promoter, the Type IV promoter/alternative exon 1, and the nextthree (3) downstream exons (here termed exon3-exon5) were used as inputinto the gRNA design software (see Muhlethaler-Mottet et al., 1997. EMBOJ. 10, 2851-2860 for CIITA gene annotation). The genomic segmentsincluded protein coding regions and flanked splicing acceptor/donorsites as well as potential gene expression regulatory elements. DesiredgRNAs were those that would lead to insertions or deletions in thecoding sequence disrupting the amino acid sequence of CIITA leading toout of frame/loss of function allele(s). Only gRNAs without a perfectmatch elsewhere in the genome were screened. From a total of ˜274 gRNAspacers targeting CIITA (identified in silico), one hundred ninety six(196) gRNA spacers were chosen for IVT screening. One hundred eighty(180) sgRNAs yielded measurable data by TIDE analysis. Eighty one (81)gRNA sequences yielded InDel percentages above 50% that could besuitable for secondary screens.

TABLE 7 CIITA target sequences, gRNA spacer sequences, and cuttingefficiencies in HEK293T cells SEQ ID gRNA Spacer SEQ ID Target SequenceNO: Sequence NO: Guide Name Indel % R² CTGGGGCCGCG 507 CUGGGGCCGC 699CIITA 93.4 0.992 GCAAGTCTG GGCAAGUCUG PIV_T19 CTCCAGTCGGT 508 CUCCAGUCGG700 CIITA 90.4 0.978 TCCTCACAG UUCCUCACAG PIV_T22 AGAGGTCTTGG 509AGAGGUCUU 701 CIITA 88.6 0.974 ATTCCTGCT GGAUUCCUGC PIV_T60 UGCCCTGCCGGT 510 GCCCUGCCGG 702 CIITA 88.4 0.943 CCTTTTCAG UCCUUUUCAGPIV_T20 AGACTCCGGGA 511 AGACUCCGGG 703 CIITA P3_T27 87.5 0.99 GCTGCTGCCAGCUGCUGCC GTCACCTACCG 512 GUCACCUACC 704 CIITA 87.1 0.97 CTGTTCCCCGCUGUUCCCC PIV_T25 GCCTGGCTCCA 513 GCCUGGCUCC 705 CIITA P3_T38 86.90.992 CGCCCTGCT ACGCCCUGCU CTGGGACTCTC 514 CUGGGACUCU 706 CIITA 86.10.99 CCCGAAGTG CCCCGAAGUG PIV_T23 GAGCTGCCACA 515 GAGCUGCCAC 707CIITA PIV_T7 84.9 0.99 GACTTGCCG AGACUUGCCG CTTGGATGCCC 516 CUUGGAUGCC708 CIITA 84.4 0.969 CAGGCAGTT CCAGGCAGUU PIV_T52 TCTGCAAGTCC 517UCUGCAAGUC 709 CIITA 84.4 0.988 TGAGTTGCA CUGAGUUGCA PIV_T58 GGGATACCGG518 GGGAUACCGG 710 CIITA 83.8 0.924 AAGAGACCAG AAGAGACCAG EXON3_T23GGTCACCTACC 519 GGUCACCUAC 711 CIITA PIVT6 83.2 0.899 GCTGTTCCCCGCUGUUCCC ACAATGCTCAG 520 ACAAUGCUCA 712 CIITA 83.1 0.943 TCACCTCACGUCACCUCAC EXON3_T14 GGAGCCCGGG 521 GGAGCCCGGG 713 CIITA 82.8 0.86GAACAGCGGT GAACAGCGGU PIV_T56 GGCCACTGTGA 522 GGCCACUGUG 714 CIITA 82.50.929 GGAACCGAC AGGAACCGAC PIV_T12 TGGAGATGCCA 523 UGGAGAUGCC 715 CIITA82.3 0.966 GCAGAAGTT AGCAGAAGU EXON5_T8 U ATAGGACCAG 524 AUAGGACCAG 716CIITA 82 0.977 ATGAAGTGAT AUGAAGUGA EXON5_T12 U CTTCTGAGCTG 525CUUCUGAGCU 717 CIITA P3_T11 81.6 0.964 GGCATCCGA GGGCAUCCGA TCCTACCTGTC526 UCCUACCUGU 718 CIITA P3_T18 81.2 0.961 AGAGCCCCA CAGAGCCCCAGCCCAGAAAA 527 GCCCAGAAAA 719 CIITA 81 0.928 GGACAATCAA GGACAAUCAAEXON4_T22 GAGGTGGTTTG 528 GAGGUGGUU 720 CIITA 80.2 0.943 CCACTTTCAUGCCACUUUC PIV_T41 A GAAGCTGAGG 529 GAAGCUGAG 721 CIITA P3_T35 80 0.942GCACGAGGAG GGCACGAGGA G GGCTTATGCCA 530 GGCUUAUGCC 722 CIITA 79.8 0.938ATATCGGTG AAUAUCGGU EXON4T1 G CTCCTCTGATG 531 CUCCUCUGAU 723 CIITA 79.70.941 CTGGCCCTA GCUGGCCCUA PIV_T46 GGATACCGGA 532 GGAUACCGGA 724 CIITA79.3 0.872 AGAGACCAGA AGAGACCAGA EXON3_T25 GGACAAGCTCC 533 GGACAAGCUC725 CIITA 78.8 0.976 CTGCAACTC CCUGCAACUC PIV_T51 CATCCATGGAA 534CAUCCAUGGA 726 CIITA 78.5 0.929 GGTACCTGA AGGUACCUGA PIV_T33 TAGCTCAGTTA535 UAGCUCAGUU 727 CIITA 77.1 0.962 GCTCATCTC AGCUCAUCUC PIV_T27GATATTGGCAT 536 GAUAUUGGC 728 CIITA 75.5 0.931 AAGCCTCCC AUAAGCCUCCEXON4_T7 C TAGTGATGAGG 537 UAGUGAUGA 729 CIITA P3_T21 74.8 0.945CTAGTGATG GGCUAGUGA UG GAAGTGGCATC 538 GAAGUGGCA 730 CIITA 74.3 0.965CCAACTGCC UCCCAACUGC PIV_T28 C GCTCAGTTAGC 539 GCUCAGUUAG 731 CIITA 74.20.985 TCATCTCAG CUCAUCUCAG PIV_T43 AGGTGATGAA 540 AGGUGAUGA 732 CIITA73.9 0.871 GAGACCAGGG AGAGACCAGG EXON4_T25 G GAGGCCACCA 541 GAGGCCACCA733 CIITA 73.3 0.987 GCAGCGCGCG GCAGCGCGCG PIV_T26 TTCTAGGGGCC 542UUCUAGGGGC 734 CIITA 73.3 0.867 CCAACTCCA CCCAACUCCA EXON3_T29AGTCTCCTCTG 543 AGUCUCCUCU 735 CIITA 72.3 0.925 TAACCCCTA GUAACCCCUAPIV_T44 AAGTGGCAAA 544 AAGUGGCAA 736 CIITA PIV_T3 72.2 0.947 CCACCTCCGAACCACCUCCG A TTTTACCTTGG 545 UUUUACCUUG 737 CIITA P3_T8 71.7 0.968GGCTCTGAC GGGCUCUGAC GGTCCATCTGG 546 GGUCCAUCUG 738 CIITA 71.5 0.881TCATAGAAG GUCAUAGAA EXON3_T6 G GAGCAACCAA 547 GAGCAACCAA 739 CIITA 71.10.887 GCACCTACTG GCACCUACUG PIV_T32 TCGTGCCCTCA 548 UCGUGCCCUC 740CIITA P3_T28 70.6 0.96 GCTTCCCCA AGCUUCCCCA ACTTCTGATAA 549 ACUUCUGAUA741 CIITA 70.4 0.939 AGCACGTGG AAGCACGUGG PIV_T17 ATGGAGTTGGG 550AUGGAGUUG 742 CIITA 68.7 0.983 GCCCCTAGA GGGCCCCUAG EXON3_T30 AAGCCCAGAAA 551 AGCCCAGAAA 743 CIITA 68.6 0.805 AGGACAATCA AGGACAAUCAEXON4_T21 TAGGGGCCCCA 552 UAGGGGCCCC 744 CIITA 68.5 0.77 ACTCCATGGAACUCCAUGG EXON3_T20 GTGGCACACTG 553 GUGGCACACU 745 CIITA 68 0.938TGAGCTGCC GUGAGCUGCC EXON3_T24 GAAGCACCTGA 554 GAAGCACCUG 746 CIITA 66.60.695 GCCCAGAAA AGCCCAGAAA EXON4_T27 GTCAGAGCCCC 555 GUCAGAGCCC 747CIITA P3_T16 65.9 0.959 AAGGTAAAA CAAGGUAAA A GCTCCAGGTAG 556 GCUCCAGGUA748 CIITA 65.8 0.856 CCACCTTCT GCCACCUUCU EXON3_T16 CTTTCACGGTT 557CUUUCACGGU 749 CIITA 65.6 0.963 GGACTGAGT UGGACUGAG PIV_T18 UGCCACTTCTGA 558 GCCACUUCUG 750 CIITA PIV_T4 65.4 0.955 TAAAGCACGAUAAAGCACG AATCCCTCAGG 559 AAUCCCUCAG 751 CIITA 64.5 0.866 TACCTTCCAGUACCUUCCA PIV_T61 GTCTGTGGCAG 560 GUCUGUGGCA 752 CIITA PIV_T1 64.40.981 CTCGTCCGC GCUCGUCCGC ACACTGTGAGC 561 ACACUGUGAG 753 CIITA 63.50.891 TGCCTGGGA CUGCCUGGGA EXON3_T38 AAAGTGGCAA 562 AAAGUGGCA 754CIITA PIV_T2 61.9 0.973 ACCACCTCCG AACCACCUCC G AGGCATCCTTG 563AGGCAUCCUU 755 CIITA P3_T32 61.6 0.95 GGGAAGCTG GGGGAAGCU G ACTCAGTCCAA564 ACUCAGUCCA 756 CIITA 61.5 0.964 CCGTGAAAG ACCGUGAAAG PIV_T11AGGGACCTCTT 565 AGGGACCUCU 757 CIITA 61.1 0.796 GGATGCCCC UGGAUGCCCCPIV_T55 AGCAAGGCTA 566 AGCAAGGCUA 758 CIITA 60.7 0.839 GGTTGGATCAGGUUGGAUC EXON5_T4 A GCCCTTGATTG 567 GCCCUUGAUU 759 CIITA 60.4 0.876TCCTTTTCT GUCCUUUUCU EXON4_T15 GGAAGGTGAT 568 GGAAGGUGA 760 CIITA 59.80.7 GAAGAGACCA UGAAGAGACC EXON4_T26 A ACCACGTGCTT 569 ACCACGUGCU 761CIITA 59.1 0.962 TATCAGAAG UUAUCAGAA PIV_T30 G ACCTTGGGGCT 570ACCUUGGGGC 762 CIITA P3_T17 58.6 0.972 CTGACAGGT UCUGACAGGU AGGTAGGACCC571 AGGUAGGACC 763 CIITA P3_T22 58.2 0.956 AGCAGGGCG CAGCAGGGCGGGGCATCCGAA 572 GGGCAUCCGA 764 CIITA P3_T2 58 0.96 GGCATCCTT AGGCAUCCUUCAGTGGCCAGC 573 CAGUGGCCAG 765 CIITA 57.6 0.804 CCCACTTCG CCCCACUUCGPIV_T36 CCCAGCCAGGC 574 CCCAGCCAGG 766 CIITA P3_T39 57.5 0.966 AGCAGCTCCCAGCAGCUCC GGCATCCGAAG 575 GGCAUCCGAA 767 CIITA P3_T10 57 0.855GCATCCTTG GGCAUCCUUG GCCTGGGACTC 576 GCCUGGGACU 768 CIITA 56.6 0.889TCCCCGAAG CUCCCCGAAG PIV_T24 CACTGTGAGGA 577 CACUGUGAGG 769 CIITA 560.876 ACCGACTGG AACCGACUGG PIV_T15 AAAAGAACTG 578 AAAAGAACU 770 CIITA55.9 0.968 CGGGGAGGCG GCGGGGAGGC PIV_T66 G TGAGCATTGTC 579 UGAGCAUUG 771CIITA 55.4 0.954 TTCCCTCCC UCUUCCCUCC EXON3_T31 C CCTCAGGTACC 580CCUCAGGUAC 772 CIITA 54.7 0.853 TTCCATGGA CUUCCAUGGA PIV_T45 CACACTGTGAG581 CACACUGUGA 773 CIITA 54.5 0.94 CTGCCTGGG GCUGCCUGGG EXON3_T36CTTCTCCAGCC 582 CUUCUCCAGC 774 CIITA 54 0.885 AGGTCCATC CAGGUCCAUCEXON3_T17 GGAAGAGACC 583 GGAAGAGACC 775 CIITA 53.5 0.958 AGAGGGAGGAAGAGGGAGG EXON3_T44 A AGCCAGGCAA 584 AGCCAGGCAA 776 CIITA P3_T1 53.40.972 CGCATTGTGT CGCAUUGUGU AAGGCTAGGTT 585 AAGGCUAGG 777 CIITA 52.60.878 GGATCAGGG UUGGAUCAG EXON5_T6 GG CCTGGGACTCT 586 CCUGGGACUC 778CIITA PIV_T9 52.3 0.745 CCCCGAAGT UCCCCGAAGU ACAGTGTGCCA 587 ACAGUGUGCC779 CIITA 51.6 0.938 CCATGGAGT ACCAUGGAGU EXON3_T4 GGCTAGGTTGG 588GGCUAGGUU 780 CIITA 50.4 0.91 ATCAGGGAG GGAUCAGGG EXON5_T11 AGCTCCAAGGCAT 589 CUCCAAGGCA 781 CIITA 50.3 0.975 GAGACTTTG UGAGACUUUPIV_T67 G GCCCCTAGAAG 590 GCCCCUAGAA 782 CIITA 50.1 0.936 GTGGCTACCGGUGGCUACC EXON3_T2 CTGACAGGTAG 591 CUGACAGGUA 783 CIITA P3_T19 48.30.952 GACCCAGCA GGACCCAGCA GCAGGGCTCTT 592 GCAGGGCUCU 784 CIITA 47.90.963 GCCACGGCT UGCCACGGCU PIV_T21 GAGCCCCAAG 593 GAGCCCCAAG 785CIITA P3_T9 47.6 0.958 GTAAAAAGGC GUAAAAAGG C GCTATTCACTC 594 GCUAUUCACU786 CIITA 47.4 0.965 CTCTGATGC CCUCUGAUGC PIV_T39 CATCGCTGTTA 595CAUCGCUGUU 787 CIITA 46.7 0.703 AGAAGCTCC AAGAAGCUCC EXON3_T1GGGTGTGGTCA 596 GGGUGUGGU 788 CIITA 46.2 0.956 TGGTAACAC CAUGGUAACAPIV_T53 C AAGTGGCATCC 597 AAGUGGCAUC 789 CIITA 45.9 0.968 CAACTGCCTCCAACUGCCU PIV_T63 GGGAAGCTGA 598 GGGAAGCUG 790 CIITA P3_T36 45.8 0.965GGGCACGAGG AGGGCACGAG G CTTCTATGACC 599 CUUCUAUGAC CIITA 45.5 0.892AGATGGACC CAGAUGGACC 791 EXON3_T11 CTCCAGGTAGC 600 CUCCAGGUAG 792 CIITA45.2 0.857 CACCTTCTA CCACCUUCUA EXON3_T7 GGAAGCTGAG 601 GGAAGCUGA 793CIITA P3_T37 45 0.86 GGCACGAGGA GGGCACGAGG A CAATGCTCAGT 602 CAAUGCUCAG794 CIITA 44.7 0.95 CACCTCACA UCACCUCACA EXON3_T27 CTTTCCCGGCC 603CUUUCCCGGC 795 CIITA P3_T14 43.7 0.931 TTTTTACCT CUUUUUACCU GCTGAACTGGT604 GCUGAACUGG 796 CIITA 43.4 0.923 CGCAGTTGA UCGCAGUUGA EXON4_T3TTGCAGATCAC 605 UUGCAGAUCA 797 CIITA 43.1 0.982 TTGCCCAAG CUUGCCCAAGPIV_T49 CTCCTCCCTCT 606 CUCCUCCCUC 798 CIITA 42.4 0.872 GGTCTCTTCUGGUCUCUUC EXON3_T42 TTCCTACACAA 607 UUCCUACACA 799 CIITA P3_T3 42.30.95 TGCGTTGCC AUGCGUUGCC TTGGGGAAGCT 608 UUGGGGAAG 800 CIITA P3_T34 420.975 GAGGGCACG CUGAGGGCAC G TCCAGGTAGCC 609 UCCAGGUAGC 801 CIITA 41.40.746 ACCTTCTAG CACCUUCUAG EXON3_T9 TGAAGTGATCG 610 UGAAGUGAU 802 CIITA39.3 0.974 GTGAGAGTA CGGUGAGAG EXON5_T1 UA CCTCTTTCCAA 611 CCUCUUUCCA803 CIITA 39.1 0.711 CACCCTGTG ACACCCUGUG EXON3_T33 ACCTCTGAAAA 612ACCUCUGAAA 804 CIITA 38.9 0.981 GGACCGGCA AGGACCGGCA PIV__T10 GTGAGGAACC613 GUGAGGAACC 805 CIITA 38.2 0.969 GACTGGAGGC GACUGGAGGC PIV_T42GGGCCATGTGC 614 GGGCCAUGUG 806 CIITA 37.5 0.976 CCTCGGAGG CCCUCGGAGGPIV_T62 AGGCTAGGTTG 615 AGGCUAGGU 807 CIITA 37.1 0.951 GATCAGGGAUGGAUCAGG EXON5_T7 GA TTCCCGGCCTT 616 UUCCCGGCCU 808 CIITA P3_T13 36.50.983 TTTACCTTG UUUUACCUUG CAGAGGTCTTG 617 CAGAGGUCUU 809 CIITA 36.10.976 GATTCCTGC GGAUUCCUGC PIV_T48 ATAGAAGTGGT 618 AUAGAAGUG 810 CIITA36.1 0.979 AGAGGCACA GUAGAGGCAC EXON3_T41 A TTCTGGGAGGA 619 UUCUGGGAG811 CIITA 35.9 0.947 AAAGTCCCT GAAAAGUCCC EXON4_T13 U TCTGACAGGTA 620UCUGACAGGU 812 CIITA P3_T7 34.8 0.981 GGACCCAGC AGGACCCAGC GCAGTTGATGG621 GCAGUUGAU 813 CIITA 34.8 0.937 TGTCTGTGT GGUGUCUGU EXON4_T19 GUCCTCACAGGGT 622 CCUCACAGGG 814 CIITA 34.4 0.952 GTTGGAAAG UGUUGGAAAEXON3_T26 G GACCGGCAGG 623 GACCGGCAGG 815 CIITA 34.3 0.943 GCTCTTGCCAGCUCUUGCCA PIV_T47 TACCGGAAGA 624 UACCGGAAGA 816 CIITA 32.7 0.982GACCAGAGGG GACCAGAGGG EXON3_T28 TGGGCATCCGA 625 UGGGCAUCCG 817CIITA P3_T4 32.5 0.983 AGGCATCCT AAGGCAUCCU GAGGAGGGGC 626 GAGGAGGGG 818CIITA P3_T25 32.1 0.982 TGCCAGACTC CUGCCAGACU C GAAATTTCCTT 627GAAAUUUCCU 819 CIITA 31.6 0.955 CTTCATCCA UCUUCAUCCA EXON4_T23AGATTGAGCTC 628 AGAUUGAGC 820 CIITA 31 0.946 TACTCAGGT UCUACUCAGGEXON3_T3 U CAGCTCACAGT 629 CAGCUCACAG 821 CIITA 30.7 0.968 GTGCCACCAUGUGCCACCA EXON3_T15 CTACCACTTCT 630 CUACCACUUC 822 CIITA 30.1 0.987ATGACCAGA UAUGACCAGA EXON3_T12 CACCTCAAAGT 631 CACCUCAAAG 823 CIITA 29.20.972 CTCATGCCT UCUCAUGCCU PIV_T68 AGGCTGTTGTG 632 AGGCUGUUG 824 CIITA28.2 0.9 TGACATGGA UGUGACAUG EXON4_T14 GA TCTGGTCATAG 633 UCUGGUCAUA 825CIITA 27.5 0.979 AAGTGGTAG GAAGUGGUA EXON3_T34 G AGTGTGCCACC 634AGUGUGCCAC 826 CIITA 27.3 0.961 ATGGAGTTG CAUGGAGUU EXON3_T18 GCAGTGTGCCAC 635 CAGUGUGCCA 827 CIITA 26.5 0.979 CATGGAGTT CCAUGGAGUUEXON3_T10 CACACAACAGC 636 CACACAACAG 828 CIITA 25.4 0.834 CTGCTGAACCCUGCUGAAC EXON4_T12 GACTCTCCCCG 637 GACUCUCCCC 829 CIITA 24.5 0.963AAGTGGGGC GAAGUGGGG PIV_T13 C CAGGGCTCTTG 638 CAGGGCUCUU 830 CIITA 24.40.958 CCACGGCTG GCCACGGCUG PIV_T64 AGGAGGGGCT 639 AGGAGGGGC 831CIITA P3_T29 24 0.989 GCCAGACTCC UGCCAGACUC C TGGTTTGCCAC 640 UGGUUUGCCA832 CIITA PIV_T8 24 0.99 TTTCACGGT CUUUCACGGU TTTCTCAAAGT 641 UUUCUCAAAG833 CIITA 23.1 0.947 AGAGCACAT UAGAGCACAU EXON5_T10 ACTTGCCGCGG 642ACUUGCCGCG 834 CIITA 22 0.991 CCCCAGAGC GCCCCAGAGC PIV_T50 TCAGTCACCTC643 UCAGUCACCU 835 CIITA 21.1 0.985 ACAGGGTGT CACAGGGUGU EXON3_T22AGGTGCTTCCT 644 AGGUGCUUCC 836 CIITA 21 0.979 CACCGATAT UCACCGAUAUEXON4_T2 TGGCACACTGT 645 UGGCACACUG 837 CIITA 20.9 0.968 GAGCTGCCTUGAGCUGCCU EXON3_T32 TGCCTGGCTCC 646 UGCCUGGCUC 838 CIITA P3_T40 20.70.988 ACGCCCTGC CACGCCCUGC CAGCAGGCTGT 647 CAGCAGGCUG 839 CIITA 20.60.981 TGTGTGACA UUGUGUGAC EXON4_T10 A GCTCCCGCGCG 648 GCUCCCGCGC 840CIITA 20.5 0.994 CGCTGCTGG GCGCUGCUGG PIV_T54 CATAGAAGTGG 649 CAUAGAAGU841 CIITA 20 0.962 TAGAGGCAC GGUAGAGGC EXON3_T19 AC CAGGGGCCATG 650CAGGGGCCAU 842 CIITA 19.3 0.984 TGCCCTCGG GUGCCCUCGG PIV_T38 CTCTCACCGAT651 CUCUCACCGA 843 CIITA 18.2 0.981 CACTTCATC UCACUUCAUC EXON5_T2AGCTTCCCCAA 652 AGCUUCCCCA 844 CIITA P3_T12 16.7 0.987 GGATGCCTTAGGAUGCCUU GACCTCTGAAA 653 GACCUCUGAA 845 CIITA PIV_T5 16.6 0.988AGGACCGGC AAGGACCGGC TGCCCTTGATT 654 UGCCCUUGAU 846 CIITA 16.6 0.911GTCCTTTTC UGUCCUUUUC EXON4_T11 AGGCTGTGTGC 655 AGGCUGUGU 847CIITA P3_T23 16.4 0.987 TTCTGAGCT GCUUCUGAGC U CAGGTGGGCCC 656CAGGUGGGCC 848 CIITA 16.1 0.987 TCCTCCCTC CUCCUCCCUC EXON3_T39AGGGAGGCTTA 657 AGGGAGGCU 849 CIITA 15.8 0.981 TGCCAATAT UAUGCCAAUAEXON4_T5 U AAACCACCTCC 658 AAACCACCUC 850 CIITA 15.5 0.165 GAGGGCACACGAGGGCACA PIV_T31 AAATTTCCTTC 659 AAAUUUCCUU 851 CIITA 14.3 0.964TTCATCCAA CUUCAUCCAA EXON4_T24 CAGTTGATGGT 660 CAGUUGAUG 852 CIITA 13.30.985 GTCTGTGTC GUGUCUGUG EXON4_T17 UC CCGGGAGCTGC 661 CCGGGAGCUG 853CIITA P3_T33 13.2 0.992 TGCCTGGCT CUGCCUGGCU GAAGAGATTG 662 GAAGAGAUU854 CIITA 12.4 0.986 AGCTCTACTC GAGCUCUACU EXON3_T8 C TGGTGTCTGTG 663UGGUGUCUG 855 CIITA 12.4 0.959 TCGGGTTCT UGUCGGGUUC EXON4_T8 UAGGCCACCAGC 664 AGGCCACCAG 856 CIITA 12.1 0.995 AGCGCGCGC CAGCGCGCGCPIV_T14 CCCACTTCGGG 665 CCCACUUCGG 857 CIITA 11.3 0.978 GAGAGTCCCGGAGAGUCCC PIV_T29 GAGGCTGTGTG 666 GAGGCUGUG 858 CIITA P3_T24 11.1 0.991CTTCTGAGC UGCUUCUGAG C CGGGCTCCCGC 667 CGGGCUCCCG 859 CIITA 10.8 0.993GCGCGCTGC CGCGCGCUGC PIV_T34 TTTCCCGGCCT 668 UUUCCCGGCC 860 CIITA P3_T209.7 0.992 TTTTACCTT UUUUUACCUU AGCTGAGGGGT 669 AGCUGAGGG 861 CIITA 8.80.981 GGGGGATAC GUGGGGGAU EXON3_T37 AC CCGGTCCTTTT 670 CCGGUCCUUU 862CIITA 8.6 0.984 CAGAGGTCT UCAGAGGUCU PIV_T37 AAGCAAGGCT 671 AAGCAAGGCU863 CIITA 8 0.965 AGGTTGGATC AGGUUGGAU EXON5_T3 C TGATTGTGTGA 672UGAUUGUGU 864 CIITA 7.7 0.974 GTTGGTCTC GAGUUGGUC EXON5_T5 UCATGGTGTCTGT 673 AUGGUGUCU 865 CIITA 6.9 0.943 GTCGGGTTC GUGUCGGGUEXON4_T6 UC AGGCAGCAGCT 674 AGGCAGCAGC 866 CIITA P3_T15 6.5 0.986CCCGGAGTC UCCCGGAGUC AGCCCCAAGGT 675 AGCCCCAAGG 867 CIITA P3_T6 5.80.995 AAAAAGGCC UAAAAAGGCC TGCTTGGTTGC 676 UGCUUGGUU 868 CIITA 5.8 0.994TCCACAGCC GCUCCACAGC PIV_T59 C ATCTGCAAGTC 677 AUCUGCAAGU 869 CIITA 5.10.995 CTGAGTTGC CCUGAGUUGC PIV_T40 ATTGTGTAGGA 678 AUUGUGUAG 870CIITA P3_T5 4.6 0.993 ATCCCAGCC GAAUCCCAGC C GGCAGGGCTCT 679 GGCAGGGCUC871 CIITA 4.2 0.985 TGCCACGGC UUGCCACGGC PIV_T16 TCCGGGAGCTG 680UCCGGGAGCU 872 CIITA P3_T30 3.9 0.993 CTGCCTGGC GCUGCCUGGC GGCATCCTTGG681 GGCAUCCUUG 873 CIITA P3_T26 3.6 0.99 GGAAGCTGA GGGAAGCUG ATATGACCAGAT 682 UAUGACCAGA 874 CIITA 3.5 0.991 GGACCTGGC UGGACCUGGCEXON3_T13 AGGGCTCTTGC 683 AGGGCUCUUG 875 CIITA 2.9 0.959 CACGGCTGGCCACGGCUGG PIV_T35 CAATCTCTTCT 684 CAAUCUCUUC 876 CIITA 1.5 0.99TCTCCAGCC UUCUCCAGCC EXON3_T40 ACCCAGCAGG 685 ACCCAGCAGG 877CIITA P3_T31 0.7 0.995 GCGTGGAGCC GCGUGGAGCC CTTTTCTGCCC 686 CUUUUCUGCC878 CIITA 0.2 0.993 AACTTCTGC CAACUUCUGC EXON5_T9 AGCTCAGTTAG 687AGCUCAGUUA 879 CIITA CTCATCTCA GCUCAUCUCA PIV_T57 AGGGAAAAAG 688AGGGAAAAA 880 CIITA AACTGCGGGG GAACUGCGGG PIV_T65 G GAGATTGAGCT 689GAGAUUGAG 881 CIITA CTACTCAGG CUCUACUCAG EXON3_T5 G GAGTTGGGGCC 690GAGUUGGGG 882 CIITA CCTAGAAGG CCCCUAGAAG EXON3_T21 G TAGAAGTGGTA 691UAGAAGUGG 883 CIITA GAGGCACAG UAGAGGCACA EXON3_T35 G AGAAGTGGTA 692AGAAGUGGU 884 CIITA GAGGCACAGG AGAGGCACAG EXON3_T43 G CGGAAGAGAC 693CGGAAGAGAC 885 CIITA CAGAGGGAGG CAGAGGGAG EXON3_T45 G TCAACTGCGAC 694UCAACUGCGA 886 CIITA CAGTTCAGC CCAGUUCAGC EXON4_T4 TGTCTGTGTCG 695UGUCUGUGUC 887 CIITA GGTTCTGGG GGGUUCUGG EXON4_T9 G GATTGTCCTTT 696GAUUGUCCUU 888 CIITA TCTGGGCTC UUCUGGGCUC EXON4_T16 AAAAGTCCCTT 697AAAAGUCCCU 889 CIITA GGATGAAGA UGGAUGAAG EXON4_T18 A TGGAAGGTGAT 698UGGAAGGUG 890 CIITA GAAGAGACC AUGAAGAGA EXON4_T20 CC

In some embodiments, a gRNA comprises the sequence of any one of SEQ IDNOs: 699-890 or targets the sequence of any one of SEQ ID NOs: 507-698.

PD1 gRNA Screen

For PDCD1 (PD1), genomic segments containing the first three (3) proteincoding exons were used as input in the gRNA design software. The genomicsegments also included flanking splice site acceptor/donor sequences.Desired gRNAs were those that would lead to insertions or deletions inthe coding sequence disrupting the amino acid sequence of PDCD1 leadingto out of frame/loss of function allele(s). One hundred ninety two (192)in silico identified gRNA spacers targeting PDCD1 were used in an IVTscreen. One hundred ninety (190) yielded measurable data by TIDEanalysis. Forty (40) gRNA sequences yielded InDel percentages above 50%that could be suitable for secondary screens.

TABLE 8PD1 target sequences, gRNA spacer sequences, and cutting efficienciesin HEK293T cells SEQ ID gRNA Spacer SEQ ID Target Sequence NO: SequenceNO: Guide Name Indel % R² TGTCTGGGGAGT 891 UGUCUGGGGAG 1083 PD1 94.70.96 CTGAGAGA UCUGAGAGA EXON2_T84 ACTGCTCAGGCG 892 ACUGCUCAGGC 1084 PD184.4 0.977 GAGGTGAGCGG GGAGGUGAG EXON1_T40 CGCAGATCAAA 893 CGCAGAUCAAA1085 PD1 83.1 0.894 GAGAGCCTG GAGAGCCUG EXON2_T51 CTGCAGCTTCTC 894CUGCAGCUUCU 1086 PD1 82.4 0.9 CAACACAT CCAACACAU EXON2_T57 GCCCTGGCCAGT895 CGCCUUCUCCA 1087 PD1 80.8 0.961 CGTCTGGGCGG CUGCUCAGG EXON1_T23CAGCGGCACCTA 896 CAGCGGCACCU 1088 PD1 77.7 0.928 CCTCTGTG ACCUCUGUGEXON2_T50 CTTCTCCACTGC 897 ACGACUGGCCA 1089 PD1 77.2 0.919 TCAGGCGGAGGGGGCGCCUG EXON1_T29 GTTGGAGAAGCT 898 GUUGGAGAAGC 1090 PD1 76.7 0.92GCAGGTGA UGCAGGUGA EXON2_T94 CGTGTCACACAA 899 CGUGUCACACA 1091 PD1 71.40.842 CTGCCCAA ACUGCCCAA EXON2_T33 CAGTGGAGAAG 900 GGAGAAGGCGG 1092 PD170.3 0.924 GCGGCACTCTGG CACUCUGGU EXON1_T19 CGCCTGAGCAGT 901 GCUCACCUCCG1093 PD1 66.6 0.885 GGAGAAGGCGG CCUGAGCAG EXON1_T37 CCCTTCGGTCAC 902CCCUUCGGUCA 1094 PD1 66.2 0.867 CACGAGCA CCACGAGCA EXON2_T14GGCGCCCTGGCC 903 UCUUAGGUAGG 1095 PD1 65.8 0.804 AGTCGTCTGGG UGGGGUCGGEXON1_T7 GTCTGGGCGGTG 904 CGACUGGCCAG 1096 PD1 65.5 0.856 CTACAACTGGGGGCGCCUGU EXON1_T3 GGAGAAGGCGG 905 CGGUGCUACAA 1097 PD1 65.1 0.945CACTCTGGTGGG CUGGGCUGG EXON1_T13 TGCCGCCTTCTC 906 CUCAGGCGGAG 1098 PD163.4 0.876 CACTGCTCAGG GUGAGCGGA EXON1_T32 GGAGTCTGAGA 907 GGAGUCUGAGA1099 PD1 63.4 0.86 GATGGAGAG GAUGGAGAG EXON2_T86 GCCCACGACACC 908GCCCACGACAC 1100 PD1 62.2 0.859 AACCACCA CAACCACCA EXON3_T17 CCAGGGAGATG909 CCAGGGAGAUG 1101 PD1 60.6 0.87 GCCCCACAG GCCCCACAG EXON2_T70GCTCACCTCCGC 910 AGGCGCCCUGG 1102 PD1 60.2 0.858 CTGAGCAGTGG CCAGUCGUCEXON1_T25 GCAGATCAAAG 911 GCAGAUCAAAG 1103 PD1 58.4 0.701 AGAGCCTGCAGAGCCUGC EXON2_T52 GGAGAAGCTGC 912 GGAGAAGCUGC 1104 PD1 58.4 0.88AGGTGAAGG AGGUGAAGG EXON2_T99 CATGAGCCCCAG 913 CAUGAGCCCCA 1105 PD1 58.10.908 CAACCAGA GCAACCAGA EXON2_T56 TGGAAGGGCAC 914 UGGAAGGGCAC 1106 PD158.1 0.786 AAAGGTCAG AAAGGUCAG EXON3_T36 GAGCCTGCGGGC 915 GAGCCUGCGGG1107 PD1 57.9 0.75 AGAGCTCA CAGAGCUCA EXON2_T72 CGCCCACGACAC 916CGCCCACGACA 1108 PD1 56 0.855 CAACCACC CCAACCACC EXON3_T8 TGGAGAAGGCG917 GAGAAGGCGGC 1109 PD1 55.6 0.743 GCACTCTGGTGG ACUCUGGUG EXON1_T20TCCAGGCATGCA 918 CAGUGGAGAAG 1110 PD1 55.5 0.725 GATCCCACAGG GCGGCACUCEXON1_T28 GACAGCGGCAC 919 GACAGCGGCAC 1111 PD1 53.6 0.794 CTACCTCTGCUACCUCUG EXON2_T44 GAGAAGGCGGC 920 GGGCGGUGCUA 1112 PD1 52.7 0.864ACTCTGGTGGGG CAACUGGGC EXON1_T18 GCTTGTCCGTCT 921 GCUUGUCCGUC 1113 PD152.5 0.584 GGTTGCTG UGGUUGCUG EXON2_T37 CCTCTGTGGGGC 922 CCUCUGUGGGG1114 PD1 52.2 0.787 CATCTCCC CCAUCUCCC EXON2_T66 TGCAGATCCCAC 923CUUCUCCACUG 1115 PD1 52.1 0.862 AGGCGCCCTGG CUCAGGCGG EXON1_T30CACTCTGGTGGG 924 UGGAGAAGGCG 1116 PD1 51.8 0.854 GCTGCTCCAGG GCACUCUGGEXON1_T36 GCAGTTGTGTGA 925 GCAGUUGUGUG 1117 PD1 51.3 0.553 CACGGAAGACACGGAAG EXON2_T25 TGTAGCACCGCC 926 UGUAGCACCGC 1118 PD1 51.1 0.93CAGACGACTGG CCAGACGAC EXON1_T1 GGCCATCTCCCT 927 GGCCAUCUCCC 1119 PD150.9 0.86 GGCCCCCA UGGCCCCCA EXON2_T88 CCTGCTCGTGGT 928 CCUGCUCGUGG 1120PD1 50.8 0.914 GACCGAAG UGACCGAAG EXON2_T13 GGGGTTCCAGGG 929 GGGGUUCCAGG1121 PD1 50.8 0.74 CCTGTCTG GCCUGUCUG EXON2_T78 GGCCAGGATGGT 930CGUCUGGGCGG 1122 PD1 50.7 0.715 TCTTAGGTAGG UGCUACAAC EXON1_T9TCAGGCGGAGGT 931 GGCCAGGAUGG 1123 PD1 48.8 0.913 GAGCGGAAGGG UUCUUAGGUEXON1_T26 TCTGGTTGCTGG 932 UCUGGUUGCUG 1124 PD1 48.7 0.76 GGCTCATGGGGCUCAUG EXON2_T69 CTTCTCCCCAGC 933 CUUCUCCCCAG 1125 PD1 48.7 0.9CCTGCTCG CCCUGCUCG EXON2_T73 CGACTGGCCAGG 934 GGUAGGUGGG 1126 PD1 48.40.868 GCGCCTGTGGG GUCGGCGGUC EXON1_T11 TTCTCTCTGGAA 935 UUCUCUCUGGA 1127PD1 48.2 0.969 GGGCACAA AGGGCACAA EXON3_T31 CCTGGCCGTCAT 936 CCUGGCCGUCA1128 PD1 48.1 0.789 CTGCTCCC UCUGCUCCC EXON3_T33 CTCCGCCTGAGC 937UGCAGAUCCCA 1129 PD1 47.2 0.948 AGTGGAGAAGG CAGGCGCCC EXON1_T38CGTTGGGCAGTT 938 CGUUGGGCAGU 1130 PD1 45.9 0.934 GTGTGACA UGUGUGACAEXON2_T30 GGATGGTTCTTA 939 GUCUGGGCGGU 1131 PD1 45.6 0.91 GGTAGGTGGGGGCUACAACU EXON1_T17 GGTTCTTAGGTA 940 CUACAACUGGG 1132 PD1 45.4 0.917GGTGGGGTCGG CUGGCGGCC EXON1_T35 CGGTCACCACGA 941 CGGUCACCACG 1133 PD145.3 0.917 GCAGGGCT AGCAGGGCU EXON2_T34 GCCTGTGGGATC 942 UGGCGGCCAGG1134 PD1 45.2 0.968 TGCATGCCTGG AUGGUUCUU EXON1_T27 CACCTACCTAAG 943GGCGCCCUGGC 1135 PD1 44 0.827 AACCATCCTGG CAGUCGUCU EXON1_T10AGGCGCCCTGGC 944 AGGAUGGUUCU 1136 PD1 43.7 0.962 CAGTCGTCTGG UAGGUAGGUEXON1_T4 GCGTGACTTCCA 945 GCGUGACUUCC 1137 PD1 42.9 0.941 CATGAGCGACAUGAGCG EXON2_T6 ACGACTGGCCAG 946 CUCCGCCUGAG 1138 PD1 42.8 0.925GGCGCCTGTGG CAGUGGAGA EXON1_T24 AGGGCCCGGCG 947 AGGGCCCGGCG 1139 PD142.3 0.902 CAATGACAG CAAUGACAG EXON2_T17 TGGCGGCCAGG 948 GCCUGUGGGAU1140 PD1 42.1 0.928 ATGGTTCTTAGG CUGCAUGCC EXONLT14 GGTGACAGGTGC 949GGUGACAGGUG 1141 PD1 41.5 0.807 GGCCTCGG CGGCCUCGG EXON2_T27GCCCTGCTCGTG 950 GCCCUGCUCGU 1142 PD1 40.3 0.877 GTGACCGA GGUGACCGAEXON2_T4 CAGTTCCAAACC 951 CAGUUCCAAAC 1143 PD1 40.1 0.908 CTGGTGGTCCUGGUGGU EXON3_T15 CGATGTGTTGGA 952 CGAUGUGUUGG 1144 PD1 39.6 0.926GAAGCTGC AGAAGCUGC EXON2_T54 GTGTCACACAAC 953 GUGUCACACAA 1145 PD1 38.60.907 TGCCCAAC CUGCCCAAC EXON2_T26 CAGGATGGTTCT 954 GCCCUGGCCAG 1146 PD138.4 0.964 TAGGTAGGTGG UCGUCUGGG EXON1_T21 CCGGGCTGGCTG 955 CCGGGCUGGCU1147 PD1 37.6 0.838 CGGTCCTC GCGGUCCUC EXON2_T38 GCTGCGGTCCTC 956GCUGCGGUCCU 1148 PD1 37.6 0.897 GGGGAAGG CGGGGAAGG EXON2_T67CGGGCTGGCTGC 957 CGGGCUGGCUG 1149 PD1 36.3 0.813 GGTCCTCG CGGUCCUCGEXON2_T36 CGCCTTCTCCAC 958 ACCGCCCAGAC 1150 PD1 36.1 0.487 TGCTCAGGCGGGACUGGCCA EXON1_T33 ACAGCGGCACCT 959 ACAGCGGCACC 1151 PD1 35.8 0.864ACCTCTGT UACCUCUGU EXON2_T42 CAAGCTGGCCGC 960 CAAGCUGGCCG 1152 PD1 35.30.945 CTTCCCCG CCUUCCCCG EXON2_T31 CTCAGCTCACCC 961 CUCAGCUCACC 1153 PD134.7 0.89 CTGCCCCG CCUGCCCCG EXON2_T77 ATGTGGAAGTCA 962 AUGUGGAAGUC 1154PD1 34.6 0.935 CGCCCGTT ACGCCCGUU EXON2_T1 GAGATGGAGAG 963 GAGAUGGAGA1155 PD1 34.4 0.885 AGGTGAGGA GAGGUGAGGA EXON2_T89 GAAGGTGGCGTT 964GAAGGUGGCGU 1156 PD1 32.4 0.976 GTCCCCTT UGUCCCCUU EXON2_T15 TGACACGGAAG965 UGACACGGAAG 1157 PD1 32.4 0.876 CGGCAGTCC CGGCAGUCC EXON2_T18ACCCTGGTGGTT 966 ACCCUGGUGGU 1158 PD1 31.3 0.465 GGTGTCGT UGGUGUCGUEXON3_T7 CTTCCACATGAG 967 CUUCCACAUGA 1159 PD1 31.1 0.962 CGTGGTCAGCGUGGUCA EXON2_T21 CCCTGCTCGTGG 968 CCCUGCUCGUG 1160 PD1 30.5 0.965TGACCGAA GUGACCGAA EXON2_T5 AGATGGAGAGA 969 AGAUGGAGAG 1161 PD1 29.90.896 GGTGAGGAA AGGUGAGGAA EXON2_T98 TCCTGGCCGTCA 970 UCCUGGCCGUC 1162PD1 29.9 0.802 TCTGCTCC AUCUGCUCC EXON3_T22 GGACCCAGACTA 971 GGACCCAGACU1163 PD1 29.8 0.819 GCAGCACC AGCAGCACC EXON3_T26 TGACGTTACCTC 972UGACGUUACCU 1164 PD1 29 0.822 GTGCGGCC CGUGCGGCC EXON3_T2 CTGAGAGATGG973 CUGAGAGAUGG 1165 PD1 27.8 0.89 AGAGAGGTG AGAGAGGUG EXON2_T81GATGGAGAGAG 974 GAUGGAGAGA 1166 PD1 27.2 0.956 GTGAGGAAG GGUGAGGAAGEXON2_T82 CACCAGGGTTTG 975 CACCAGGGUUU 1167 PD1 25.9 0.896 GAACTGGCGGAACUGGC EXON3_T24 GCAGGGCTGGG 976 GCAGGGCUGGG 1168 PD1 25.2 0.966GAGAAGGTG GAGAAGGUG EXON2_T96 GGCTCAGCTCAC 977 GGCUCAGCUCA 1169 PD1 24.80.955 CCCTGCCC CCCCUGCCC EXON2_T106 AACTGGGCTGGC 978 CACCUACCUAA 1170PD1 23.9 0.969 GGCCAGGATGG GAACCAUCC EXON1_T34 AGCAGGGCTGG 979AGCAGGGCUGG 1171 PD1 23.8 0.807 GGAGAAGGT GGAGAAGGU EXON2_T85ACATGAGCGTGG 980 ACAUGAGCGUG 1172 PD1 23.7 0.984 TCAGGGCC GUCAGGGCCEXON2_T41 TCGGTCACCACG 981 UCGGUCACCAC 1173 PD1 23.5 0.954 AGCAGGGCGAGCAGGGC EXON2_T28 GGGCCCTGACCA 982 GGGCCCUGACC 1174 PD1 23.3 0.976CGCTCATG ACGCUCAUG EXON2_T22 CGTCTGGGCGGT 983 CACCGCCCAGA 1175 PD1 23.20.967 GCTACAACTGG CGACUGGCC EXON1_T2 CTGGCTGCGGTC 984 CUGGCUGCGGU 1176PD1 22.8 0.963 CTCGGGGA CCUCGGGGA EXON2_T39 TTTGTGCCCTTC 985 UUUGUGCCCUU1177 PD1 22.4 0.87 CAGAGAGA CCAGAGAGA EXON3_T38 AGGATGGTTCTT 986CGCCUGAGCAG 1178 PD1 22.2 0.968 AGGTAGGTGGG UGGAGAAGG EXONLT16GGTGCTGCTAGT 987 GGUGCUGCUAG 1179 PD1 22.1 0.937 CTGGGTCC UCUGGGUCCEXON3_T16 GGCACTTCTGCC 988 GGCACUUCUGC 1180 PD1 21.6 0.926 CTTCTCTCCCUUCUCUC EXON3_T37 ACAAAGGTCAG 989 ACAAAGGUCAG 1181 PD1 20.9 0.895GGGTTAGGA GGGUUAGGA EXON3_T40 TTCTGCCCTTCT 990 UUCUGCCCUUC 1182 PD1 20.50.951 CTCTGGAA UCUCUGGAA EXON3_T42 CATGTGGAAGTC 991 CAUGUGGAAGU 1183 PD120.3 0.979 ACGCCCGT CACGCCCGU EXON2_T2 GTGCGGCCTCGG 992 GUGCGGCCUCG 1184PD1 20.2 0.99 AGGCCCCG GAGGCCCCG EXON2_T40 GATCTGCGCCTT 993 GAUCUGCGCCU1185 PD1 20 0.977 GGGGGCCA UGGGGGCCA EXON2_T49 GGGCGGTGCTAC 994CACUCUGGUGG 1186 PD1 18.4 0.981 AACTGGGCTGG GGCUGCUCC EXON1_T8GAGGTGAGGAA 995 GAGGUGAGGA 1187 PD1 18.2 0.963 GGGGCTGGG AGGGGCUGGGEXON2_T105 ACGGAAGCGGC 996 ACGGAAGCGGC 1188 PD1 18.1 0.986 AGTCCTGGCAGUCCUGGC EXON2_T35 CTGGAAGGGCA 997 CUGGAAGGGCA 1189 PD1 18.1 0.963CAAAGGTCA CAAAGGUCA EXON3_T32 GAGGGGCTGGG 998 GAGGGGCUGGG 1190 PD1 17.50.94 GTGGGCTGT GUGGGCUGU EXON3_T44 ACTTCCACATGA 999 ACUUCCACAUG 1191 PD117.4 0.984 GCGTGGTC AGCGUGGUC EXON2_T10 GGTCACCACGAG 1000 GGUCACCACGA1192 PD1 17.4 0.989 CAGGGCTG GCAGGGCUG EXON2_T55 CGCCTTGGGGGC 1001CGCCUUGGGGG 1193 PD1 17.2 0.933 CAGGGAGA CCAGGGAGA EXON2_T103AGCCGGCCAGTT 1002 AGCCGGCCAGU 1194 PD1 17.1 0.972 CCAAACCC UCCAAACCCEXON3_T12 TGCGGCCCGGGA 1003 UGCGGCCCGGG 1195 PD1 16.6 0.954 GCAGATGAAGCAGAUGA EXON3_T23 CCCGAGGACCGC 1004 CCCGAGGACCG 1196 PD1 16.1 0.96AGCCAGCC CAGCCAGCC EXON2_T63 GTAACGTCATCC 1005 GUAACGUCAUC 1197 PD1 15.60.957 CAGCCCCT CCAGCCCCU EXON3_T25 GGTGTCGTGGGC 1006 GGUGUCGUGGG 1198PD1 15.3 0.982 GGCCTGCT CGGCCUGCU EXON3_T14 ATCTCTCAGACT 1007AUCUCUCAGAC 1199 PD1 14.4 0.988 CCCCAGAC UCCCCAGAC EXON2_T48GGTAGGTGGGGT 1008 GGAUGGUUCUU 1200 PD1 13.7 0.973 CGGCGGTCAGG AGGUAGGUGEXON1_T12 AGGTGCCGCTGT 1009 AGGUGCCGCUG 1201 PD1 13.5 0.982 CATTGCGCUCAUUGCGC EXON2_T11 TGGGATGACGTT 1010 UGGGAUGACGU 1202 PD1 13.2 0.964ACCTCGTG UACCUCGUG EXON3_T1 TCACCCTGAGCT 1011 UCACCCUGAGC 1203 PD1 12.50.974 CTGCCCGC UCUGCCCGC EXON2_T62 CGGCCAGTTCCA 1012 CGGCCAGUUCC 1204PD1 12.1 0.97 AACCCTGG AAACCCUGG EXON3_T20 GCTCAGCTCACC 1013 GCUCAGCUCAC1205 PD1 12 0.148 CCTGCCCC CCCUGCCCC EXON2_T90 CGGGCAGAGCTC 1014CGGGCAGAGCU 1206 PD1 10.9 0.98 AGGGTGAC CAGGGUGAC EXON2_T58 GGTGCCGCTGTC1015 GGUGCCGCUGU 1207 PD1 10.7 0.987 ATTGCGCC CAUUGCGCC EXON2_T12GCAGCCTGGTGC 1016 GCAGCCUGGUG 1208 PD1 10.7 0.95 TGCTAGTC CUGCUAGUCEXON3_T19 TGGAACTGGCCG 1017 UGGAACUGGCC 1209 PD1 10.6 0.974 GCTGGCCTGGCUGGCCU EXON3_T27 GAGCAGGGCTG 1018 GAGCAGGGCUG 1210 PD1 10.3 0.97GGGAGAAGG GGGAGAAGG EXON2_T100 CACGAGCAGGG 1019 CACGAGCAGGG 1211 PD110.2 0.977 CTGGGGAGA CUGGGGAGA EXON2_T95 GGACCGCAGCC 1020 GGACCGCAGCC1212 PD1 10 0.97 AGCCCGGCC AGCCCGGCC EXON2_T74 CAGGGCTGGGG 1021CAGGGCUGGGG 1213 PD1 10 0.956 AGAAGGTGG AGAAGGUGG EXON2_T97 CCCCTTCGGTCA1022 CCCCUUCGGUC 1214 PD1 9.8 0.993 CCACGAGC ACCACGAGC EXON2_T8ATCTGCTCCCGG 1023 AUCUGCUCCCG 1215 PD1 9.8 0.982 GCCGCACG GGCCGCACGEXON3_T5 CTTCTGCCCTTC 1024 CUUCUGCCCUU 1216 PD1 9.7 0.992 TCTCTGGACUCUCUGGA EXON3_T46 AGCTTGTCCGTC 1025 AGCUUGUCCGU 1217 PD1 9.6 0.995TGGTTGCT CUGGUUGCU EXON2_T19 CCTCGGAGGCCC 1026 CCUCGGAGGCC 1218 PD1 9.30.933 CGGGGCAG CCGGGGCAG EXON2_T76 AGGCGGCCAGCT 1027 AGGCGGCCAGC 1219PD1 9.1 0.991 TGTCCGTC UUGUCCGUC EXON2_T9 AGGGTTTGGAAC 1028 AGGGUUUGGA1220 PD1 9.1 0.965 TGGCCGGC ACUGGCCGGC EXON3_T6 AGAGCCTGCGG 1029AGAGCCUGCGG 1221 PD1 8.8 0.984 GCAGAGCTC GCAGAGCUC EXON2_T59 CAACCACCAGG1030 CAACCACCAGG 1222 PD1 8.8 0.967 GTTTGGAAC GUUUGGAAC EXON3_T21TCTGGAAGGGCA 1031 UCUGGAAGGGC 1223 PD1 8.8 0.984 CAAAGGTC ACAAAGGUCEXON3_T28 GGCCTCGGAGGC 1032 GGCCUCGGAGG 1224 PD1 8.6 0.969 CCCGGGGCCCCCGGGGC EXON2_T102 AGAGCTCAGGGT 1033 AGAGCUCAGGG 1225 PD1 8.4 0.087GACAGGTG UGACAGGUG EXON2_T93 CGGTGCTACAAC 1034 UCCAGGCAUGC 1226 PD1 8.30.985 TGGGCTGGCGG AGAUCCCAC EXON1_T22 CAGCCTGGTGCT 1035 CAGCCUGGUGC 1227PD1 8.2 0.977 GCTAGTCT UGCUAGUCU EXON3_T29 GGAGATGGCCCC 1036 GGAGAUGGCCC1228 PD1 8.1 0.089 ACAGAGGT CACAGAGGU EXON2_T60 AAAGGTCAGGG 1037AAAGGUCAGGG 1229 PD1 8.1 0.987 GTTAGGACG GUUAGGACG EXON3_T18 CAAAGGTCAGG1038 CAAAGGUCAGG 1230 PD1 7.8 0.983 GGTTAGGAC GGUUAGGAC EXON3_T34CTGGTGGTTGGT 1039 CUGGUGGUUGG 1231 PD1 7.7 0.984 GTCGTGGG UGUCGUGGGEXON3_T30 CCCGGGAGCAG 1040 CCCGGGAGCAG 1232 PD1 7.5 0.986 ATGACGGCCAUGACGGCC EXON3_T10 CGGAGAGCTTCG 1041 CGGAGAGCUUC 1233 PD1 7.3 0.994TGCTAAAC GUGCUAAAC EXON2_T3 CACGAAGCTCTC 1042 CACGAAGCUCU 1234 PD1 70.993 CGATGTGT CCGAUGUGU EXON2_T7 CCCCTGCCCCGG 1043 CCCCUGCCCCG 1235 PD17 0.992 GGCCTCCG GGGCCUCCG EXON2_T83 GGGCTGGGGAG 1044 GGGCUGGGGAG 1236PD1 6.7 0.974 AAGGTGGGG AAGGUGGGG EXON2_T101 GAGAGAGGTGA 1045 GAGAGAGGUG1237 PD1 6.6 0.982 GGAAGGGGC AGGAAGGGGC EXON2_T92 GGGGGGTTCCAG 1046GGGGGGUUCCA 1238 PD1 6.5 0.963 GGCCTGTC GGGCCUGUC EXON2_T68 TGGTGTCGTGGG1047 UGGUGUCGUGG 1239 PD1 6.2 0.983 CGGCCTGC GCGGCCUGC EXON3_T13AGGGCTGGGGA 1048 AGGGCUGGGGA 1240 PD1 5.5 0.992 GAAGGTGGG GAAGGUGGGEXON2_T91 GGTGCGGCCTCG 1049 GGUGCGGCCUC 1241 PD1 5.3 0.99 GAGGCCCCGGAGGCCCC EXON2_T64 AGCCCCTCACCC 1050 AGCCCCUCACC 1242 PD1 5.3 0.99AGGCCAGC CAGGCCAGC EXON3_T41 CTCAGGCGGAG 1051 GGUUCUUAGGU 1243 PD1 5.20.99 GTGAGCGGAAG AGGUGGGGU EXONl_T39 G AGCGGCAGTCCT 1052 AGCGGCAGUCC1244 PD1 5.2 0.981 GGCCGGGC UGGCCGGGC EXON2_T43 GGGCACAAAGG 1053GGGCACAAAGG 1245 PD1 5.2 0.99 TCAGGGGTT UCAGGGGUU EXON3_T35 CAGCTTGTCCGT1054 CAGCUUGUCCG 1246 PD1 5.1 0.996 CTGGTTGC UCUGGUUGC EXON2_T16CCTGGGTGAGGG 1055 CCUGGGUGAGG 1247 PD1 4.8 0.995 GCTGGGGT GGCUGGGGUEXON3_T45 CGACACCAACCA 1056 CGACACCAACC 1248 PD1 4.7 0.992 CCAGGGTTACCAGGGUU EXON3_T9 CGGAAGCGGCA 1057 CGGAAGCGGCA 1249 PD1 4.4 0.995GTCCTGGCC GUCCUGGCC EXON2_T46 TTGGAACTGGCC 1058 UUGGAACUGGC 1250 PD1 4.30.989 GGCTGGCC CGGCUGGCC EXON3_T11 GGAGAAGGTGG 1059 GGAGAAGGUG 1251 PD14.2 0.989 GGGGGTTCC GGGGGGUUCC EXON2_T80 ACCGCCCAGACG 1060 CAGGAUGGUUC1252 PD1 4.1 0.984 ACTGGCCAGGG UUAGGUAGG EXON1_T5 GAGAAGGTGGG 1061GAGAAGGUGG 1253 PD1 3.8 0.987 GGGGTTCCA GGGGGUUCCA EXON2_T65CTGGCCGGCTGG 1062 CUGGCCGGCUG 1254 PD1 3.5 0.991 CCTGGGTG GCCUGGGUGEXON3_T43 CTACAACTGGGC 1063 UGCCGCCUUCU 1255 PD1 3.2 0.981 TGGCGGCCAGGCCACUGCUC EXON 1_T15 TCTTAGGTAGGT 1064 AACUGGGCUGG 1256 PD1 3.1 0.98GGGGTCGGCGG CGGCCAGGA EXON1_T31 GGGGGTTCCAGG 1065 GGGGGUUCCAG 1257 PD13.1 0.993 GCCTGTCT GGCCUGUCU EXON2_T75 CACCGCCCAGAC 1066 UCAGGCGGAGG1258 PD1 2.9 0.979 GACTGGCCAGG UGAGCGGAA EXON1_T6 CTCTTTGATCTG 1067CUCUUUGAUCU 1259 PD1 2.5 0.979 CGCCTTGG GCGCCUUGG EXON2_T32 GCCGGGCTGGCT1068 GCCGGGCUGGC 1260 PD1 2.5 0.996 GCGGTCCT UGCGGUCCU EXON2_T53AGGTGCGGCCTC 1069 AGGUGCGGCCU 1261 PD1 2.2 0.989 GGAGGCCC CGGAGGCCCEXON2_T61 TGATCTGCGCCT 1070 UGAUCUGCGCC PD1 2.1 0.997 TGGGGGCC UUGGGGGCC1262 EXON2_T45 CAGACTCCCCAG 1071 CAGACUCCCCA 1263 PD1 2 0.992 ACAGGCCCGACAGGCCC EXON2_T104 CAGCAACCAGA 1072 CAGCAACCAGA 1264 PD1 1.9 0.996CGGACAAGC CGGACAAGC EXON2_T24 TCTCTTTGATCT 1073 UCUCUUUGAUC 1265 PD1 1.90.994 GCGCCTTG UGCGCCUUG EXON2_T29 TTGTGCCCTTCC 1074 UUGUGCCCUUC 1266PD1 1.9 0.993 AGAGAGAA CAGAGAGAA EXON3_T39 AGTCCTGGCCGG 1075 AGUCCUGGCCG1267 PD1 1.4 0.996 GCTGGCTG GGCUGGCUG EXON2_T79 AGAGAGGTGAG 1076AGAGAGGUGA 1268 PD1 1.2 0.993 GAAGGGGCT GGAAGGGGCU EXON2_T87GCTCTCTTTGAT 1077 GCUCUCUUUGA 1269 PD1 1 0.992 CTGCGCCT UCUGCGCCUEXON2_T20 CAGGGTGACAG 1078 CAGGGUGACAG 1270 PD1 0.8 0.993 GTGCGGCCTGUGCGGCCU EXON2_T47 GCCTCGGAGGCC 1079 GCCUCGGAGGC 1271 PD1 0.2 0.993CCGGGGCA CCCGGGGCA EXON2_T71 CTCTCTTTGATC 1080 CUCUCUUUGAU 1272 PD1 0.10.994 TGCGCCTT CUGCGCCUU EXON2_T23 GACGTTACCTCG 1081 GACGUUACCUC 1273PD1 TGCGGCCC GUGCGGCCC EXON3_T3 AACCCTGGTGGT 1082 AACCCUGGUGG 1274 PD1TGGTGTCG UUGGUGUCG EXON3_T4

In some embodiments, a gRNA comprises the sequence of any one of SEQ IDNOs: 1083-1275 or comprises a sequence that targets the sequence of anyone of SEQ ID NOs: 891-1082.

PD1 Screen in SpCas9/HEK293T Cells and T Cells

Five (5) PD1 gRNAs were selected for further analysis in HEK293T cellsand T cells. Three out of the five guides performed better (higher indelpercentage) than the positive control (PD1 control). Surprisingly, theguide producing the highest indel percentage (editing frequency) (Guide2) did not produce the greatest level of PD1 protein expressionknockdown (compared to Guides 3-5—see Table 9).

TABLE 9 PD1 gRNA spacer sequences SEQ Indel PD1+ ID Indel T TgRNA sequence NO: HEK cell cells Cas9 — — — — 44.7% only PD1CGCCCACGACACCAACCACC 1108 56.0% 70.7% 19.0% control Guide 1UGUCUGGGGAGUCUGAGAGA 1083 94.7% 86.4% 31.7% Guide 2 ACUGCUCAGGCGGAGGUGAG1084 84.4% 99.5% 44.4% Guide 3 CGCAGAUCAAAGAGAGCCUG 1085 83.1% 60.3%4.76% Guide 4 CUGCAGCUUCUCCAACACAU 1086 82.4% 92.7% 0.24% Guide 5GCCCUGGCCAGUCGUCUGGG 1146 80.8% 99.0% 0.31%

A homology-dependent assessment of the PD1 gRNAs of Table 9 showed thatPD1 Guide 5 (comprising SEQ ID NO: 1276) had an indel frequency of 20%at an off-target site, while PD1 Guide 4 (SEQ ID NO: 1086) had an indelfrequency of less than 2.0% at an off-target site. This data guidedselection of PD1 Guide 4 for further analysis.

CTLA-4 Screen in T Cells

One (1) million T cells were electroporated with 1000 pmol gRNA and 200pmol Cas9 protein. 48-72 hours post-EP, cells were stimulated with aPMA/ionomycin cocktail solution and simultaneously stained with CTLA4antibody (1:100 dilution, Biolegend #349907). Four (4) hourspost-stimulation, cells were collected for FACS analysis. Two differentdonors were used (Donor 46 and Donor 13). Protein expression wasmeasured by flow cytometry. The results are shown in Table 10. Use ofGuide 5 (with spacer SEQ ID NO: 1292) consistently resulted in thelowest protein expression (e.g., 8.6%). Use of Guide 2 (with spacer SEQID NO: 1290) and Guide 9 (with spacer SEQ ID NO: 1297) also resulted inlow protein expression (11.9% and 12.2%, respectively).

TABLE 10 CTLA-4 target and gRNA spacer sequences Donor46 Target SpacerPAM CCTop Donor46 Donor13 Protein Sequence Sequence (NGG) (Raw) *Indel (%) Indel (%) (%) CTLA-4 TGCCCAGGT UGCCCAGG GGG −157 85.6 73.19.08 Control AGTATGGCG UAGUAUGG GT (SEQ ID CGGU (SEQ NO: 1277)ID NO: 1288) Guide 1 ACACCGCTC ACACCGCU TGG −662 93.5 91.1 57.6CCATAAAGC CCCAUAAA CA (SEQ ID GCCA (SEQ NO: 1278) ID NO: 1289) Guide 2TGGCTTGCC UGGCUUGC CGG −1537.8 89.4 85.6 11.9 TTGGATTTC CUUGGAUUAG (SEQ ID UCAG (SEQ NO: 1279) ID NO: 1290) Guide 3 GCACAAGGC GCACAAGGTGG −5276.6 90.8 81.7 17.3 TCAGCTGAA CUCAGCUG CC (SEQ ID AACC (SEQNO: 1280) ID NO: 1291) Guide 4 TTCCATGCT UUCCAUGC TGG −967.3 77.7 42.221.3 AGCAATGCA UAGCAAUG CG (SEQ ID CACG (SEQ NO: 1281) ID NO: 1292)Guide 5 GCACGTGGC GCACGUGG TGG −2387.2 91.9 82.9 8.6 CCAGCCTGC CCCAGCCUTG (SEQ ID GCUG (SEQ NO: 1282) ID NO: 1293) Guide 6 GTGGTACTG GUGGUACUAGG −1048.4 85.1 51.5 27.6 GCCAGCAGC GGCCAGCA CG (SEQ ID GCCG (SEQNO: 1283) ID NO: 1294) Guide 7 GTGTGTGAG GUGUGUGA AGG −1299.5 93.9 59.114.6 TATGCATCT GUAUGCAU CC (SEQ ID CUCC (SEQ NO: 1284) ID NO: 1295)Guide 8 AGGACTGAG AGGACUGA CGG −1624.6 76.1 64.4 12.2 GGCCATGGA GGGCCAUGCA (SEQ ID GACA (SEQ NO: 1285) ID NO: 1296) Guide 9 TCCTTGCAG UCCUUGCAGGG −242.2 95.5 90.9 12.2 CAGTTAGTT GCAGUUAG CG (SEQ ID UUCG (SEQNO: 1286) ID NO: 1297) Guide TCAGAATCT UCAGAAUC TGG −516.9 93.6 54.137.9 10 GGGCACGGT UGGGCACG TC (SEQ ID GUUC (SEQ NO: 1287) ID NO: 1298)

Example 2—Gene Knockout at Genotypic and Phenotypic Levels in Cells

This example demonstrates efficient knockout by CRISPR/Cas9 of Graft vs.Host (GVH) or Host vs. Graft (HVG) or Immune checkpoint genes at thegenotypic and phenotypic levels in primary human T cells.

Primary human T cells were isolated from peripheral blood (AllCells,Alameda, Calif.) using EasySep Direct Human T Cell Isolation Kit(Stemcell Technologies, Vancouver, Canada). The cells were plated at0.5×10⁶ cells/mL in large flasks. Human T-Activator CD3/CD28 Dynabeads(Thermo Fisher Scientific, Waltham, Mass.) were resuspended and washedwith PBS prior to adding to the cells. The cells were incubated withHuman T-Activator CD3/CD28 Dynabeads (Thermo Fisher Scientific, Waltham,Mass.) at a bead-to-cell ratio of 1:1 in X-vivo 15 hematopoieticserum-free medium (Thermo Fisher Scientific, Waltham, Mass.)supplemented with 5% human serum (Sigma-Aldrich, St. Louis, Mo.), 50ng/mL human recombinant IL-2 (Peprotech, Rocky Hill, N.J.), and 10 ng/mLhuman recombinant IL-7 (Thermo Fisher Scientific, Waltham, Mass.). After3 days, the cells were transferred to a 15 mL tube and the beads wereremoved by placing the tube on a magnet for 5 mins. Cells were thentransferred, pelleted and plated at 0.5×10⁶ cells/mL.

Three (3) days after beads were removed, T cells were electroporatedusing the 4D-Nucleofector (program E0115) (Lonza, Walkersville, Md.) andHuman T Cells Nucleofector Kit (Lonza, Walkersville, Md.). Thenucleofection mix contained the Nucleofector Solution, 10⁶ cells, 1 μMCas9 (Feldan, Québec, Canada), and 5 μM 2′-O-methyl 3′ phosphorothioate(MS) modified sgRNA (TriLink BioTechonologies, San Diego, Calif.) (Asdescribed in Hendel et al., 2015: PMID: 26121415). The MS modificationwas incorporated at three nucleotides at both the 5′ and 3′ ends. Toallow for stable Cas9:sgRNA ribonucleoproteins (RNPs) formation, Cas9was pre-incubated with sgRNAs in a Cas9:sgRNA molar ratio of 1:5 at 37°C. for 10 min prior to adding the nucleofection mix. For multiplexediting experiments, 1 μM (final concentration) each of Cas9pre-complexed individually with sgRNAs was added to the electroporationbuffer mix. Typical controls for each experiment included:non-electroporated cells, one mock treatment without the RNPs, onetreatment with Cas9 alone and one treatment with MS modified AAVS1 sgRNAto monitor transfection efficiency. Following nucleofection, the cellswere incubated at 37° C. for 4-7 days and analyzed by flow cytometry forsurface protein expression and Tracking of InDels by Decomposition(TIDE) for insertions or deletions (InDels) on genomic DNA.

TIDE is a web tool to rapidly assess genome editing by CRISPR/Cas9 oftarget locus determined by a guide RNA (gRNA or sgRNA). Based onquantitative sequence trace data from two standard capillary sequencingreactions, the TIDE software quantifies the editing efficacy andidentifies the predominant types of insertions and deletions (InDels) inthe DNA of a targeted cell pool.

This example and the following example tested sgRNAs delivered by RNP.The sgRNA sequence comprise a 20 nucleotide spacer sequence (indicatedin each example) followed by a backbone sequence. Table 11 lists targetsequences specific to the indicated gene that were used as sgRNAs insynthetic and modified form that when complexed with Cas9 proteinproduced the indicated InDel % in primary human T cells. Table 11 listsInDel frequencies for synthetic and/modified sgRNA sequences (deliveredas RNPs) targeting the indicated genes and target sequences in primaryhuman T cells.

Examples of backbone sequences are shown in Table 1.

TABLE 11 Indel frequencies SEQ ID % InDel in T Cells NO: GeneTarget Sequence (Synthetic Guides) 76 TRAC AGAGCAACAGTGCTGTGGCC 72 1299TRAC GGCTCTCGGAGAATGACGAG 61 962 PD1 ATGTGGAAGTCACGCCCGTT 25 916 PD1CGCCCACGACACCAACCACC 53 1300 PD1 CGACTGGCCAGGGCGCCTGT 48.4 1277 CTLA4TGCCCAGGTAGTATGGCGGT 40 417 B2M GCTACTCTCTCTTTCTGGCC 91 1301 AAVS1GGGGCCACTAGGGACAGGAT 75 1302 AAVS1 GCCAGTAGCCAGCCCCGTCC 40 546 CIITAGGTCCATCTGGTCATAGAAG 81 1303 CD52 TTACCTGTACCATAACCAGG 83 1304 CD52CCTACTCACCATCAGCCTCC 87 226 CD3E GGGCACTCACTGGAGAGTTC 67 222 CD3ETAAAAACATAGGCGGTGATG 68 1305 RFX5 TACCTCGGAGCCTCTGAAGA 88 1306 RFX5TGTGCTCTTCCAGGTGGTTG 87 1307 RFX5 ATCAAAGCTCGAAGGCTTGG 70

Example 3—Editing TCR Components in Cells

This example demonstrates the in vitro functional consequences inprimary human T cells of editing TCR components (TCRa and CD3c). Theresults of which are shown in FIGS. 6A and 6B.

For flow cytometry experiments, approximately 0.5×10⁶ to 1×10⁶ RNPtransfected cells were removed from culture 4-6 days postelectroporation and transferred to a clean Eppendorf tube. Cells werepelleted by centrifugation at 1,200 rpm for 5 min and resuspended in 100μL FACS buffer (0.5% BSA/PBS). To stain the cells, appropriate antibodycocktail was added to the sample, followed by incubation for 10-15 minat room temperature. UltraComp eBeads (Ebioscience, San Diego, Calif.)were used for preparing compensation controls along with the specificconjugated antibody when necessary. The compensation beads were stainedat 1:100 with individual specific primary antibody used in theexperiment for about 5 min. Stained samples (including compensationcontrols) were washed with 1 mL FACS buffer, centrifuged at 1,200 rpm,and aspirated to remove the buffer. Compensation beads were resuspendedin 200 μL FACS buffer and passed through a 5 mL FACS tube with a cellstrainer cap (Corning Inc., Corning, N.Y.). Cell samples wereresuspended in 200 μL FACS buffer containing 1:1000 7AAD (Thermo FisherScientific, Waltham, Mass.), and passed through a 5 mL FACS tube with acell strainer cap. Samples were then examined on NovoCyte ACEA 3000 flowcytometer (ACEA Biosciences, San Diego, Calif.) using the automaticcompensation software and data was analyzed on Flowjo10.1r5. Antibodiesused include BV510 anti-human CD3 (UCHT1, BioLegend, San Diego, Calif.),PE anti-human TCRαβ (BW242/412, Miltenyi Biotec, Auburn, Calif.), PE/Cy7anti-human CD8 (SK1, BioLegend, San Diego, Calif.), and APC/Cy7anti-human CD4 (RPA-T4, BioLegend, San Diego, Calif.).

Without being bound by theory, the reason for disrupting TCR intherapeutic T cells was that these T cells would not signal throughupstream stimuli to the TCR, and thus not react with recipientpeptides/antigens, but would maintain their ability to respond todownstream TCR signaling even after TCR knock-out. Phytohemagglutanin(PHA) and phorbol myristate acetate (PMA)/Ionomycin are two commonlyused stimulation regimens for in vitro T cell activation, but they actthrough distinct mechanisms. PHA is a mitogenic lectin that activatesthe cells by crosslinking the TCR/CD3 complex as well as otherglycosylated membrane proteins. On the contrary, PMA/Ionomycinstimulates T cells by directly activating TCR downstream pathways,bypassing the need for surface receptor stimulation. Therefore, TCR/CD3deficient T cells were expected to react to PMA/Ionomycin but not toPHA.

To assess the function of TCR ablated T cells, primary human T cellswere edited with CRISPR/Cas9 to disrupt TCR components TCRα or CD3ε,treated with the two stimulation regimens, and tested for activation,proliferation, degranulation, and cytokine production using a series ofassays described below. Primary human T cells were first electroporatedwith Cas9 or Cas9:sgRNA RNP complexes targeting AAVS1(GGGGCCACTAGGGACAGGAT (SEQ ID NO: 1301)), TRAC (AGAGCAACAGTGCTGTGGCC(SEQ ID NO: 76)), or CD3ε (GGGCACTCACTGGAGAGTTC (SEQ ID NO: 226)). Six(6) days post transfection, cells were stained for CD3ε and thepercentage of cells with low or absent levels of CD3ε were assessed byflow cytometry. The results showed that transfection with Cas9:TRACsgRNA or Cas9:CD3ε sgRNA largely reduced surface presentation of CD3.The CD3⁻ population in Cas9:TRAC sgRNA and Cas9:CD3ε sgRNA transfectedcells was 89% and 81%, respectively, whereas the percentage were 10% and5% in Cas9 only or Cas9:AAVS1 sgRNA transfected cells. This confirmedthat the CRISPR/Cas9 edited cells had deficient TCR/CD3 complexes. Thesecells served as inputs for the assessment in the subsequent assayexperiments. The gRNAs used in this Example comprise the followingspacer sequences:

AAVS1 gRNA spacer (SEQ ID NO: 1308) (GGGGCCACUAGGGACAGGAU),TRAC gRNA spacer (SEQ ID NO: 152) (AGAGCAACAGUGCUGUGGCC), andCD3ε gRNA spacer (SEQ ID NO: 351) (GGGCACUCACUGGAGAGUUC).

CD69 Activation Assay

CD69 is a surrogate marker of T-cell responsiveness to mitogen andantigen stimulus and is used as a measure of T-cell activation. 7 dayspost transfection, cells were stimulated with either PHA-L (Ebioscience,San Diego, Calif.) or PMA/Ionomycin and grown for additional 2 days.Cells were then stained with APC mouse anti-human CD69 antibody (L78, BDBiosciences, San Jose, Calif.) and the levels of CD69 were assayed byflow cytometry (FIG. 6A). Control cells that received neither PHA norPMA/Ionomycin treatment had little CD69 expression, suggesting there wasno T-cell activation. Cells with intact TCR/CD3 complexes (Mocktransfected[−], Cas9 alone, and Cas9:AAVS1 sgRNA transfected groups)displayed induced expression of CD69 after either PHA or PMA/Ionomycintreatment albeit to varying degrees. In contrast, neither cells treatedwith Cas9:TRAC (targeting AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 76)), norcells treated with Cas9: CD3ε (targeting GGGCACTCACTGGAGAGTTC (SEQ IDNO: 226)), showed induced CD69 expression after PHA treatment,indicating that the TCR/CD3ε complex was disrupted within these cells.However, both treatment groups exhibited strong expression of CD69 afterPMA/Ionomycin treatment (FIG. 6A). This demonstrated that the TCR/CD3deficient T cells show blunted responses to TCR agonists, but retainedability to be activated with signals downstream of the TCR.

CFSE Proliferation Assay

To further examine cell proliferation in TCR/CD3 deficient cells, theresponse to PHA and PMA/Ionomycin in the TCR/CD3 deficient cells wasassessed. Carboxyfluorescein succinimidyl ester (CFSE) is acell-permeant fluorescein-based dye used for monitoring lymphocyteproliferation. After transfection, the cells were labeled with 500 nMCFSE for 15 min at 37° C. After washing, cells were plated in serum andcytokine free media for 4 days. CFSE levels were measured by flowcytometry in the FITC channel (FIG. 6A). Control cells that receivedneither PHA nor PMA/Ionomycin treatment showed CFSE intensity expectedof non-divided cells. Both PHA and PMA/Ionomycin treatment caused ashift in CFSE intensity in Mock transfected cells (Cas9 alone) andCas9:AAVS1 sgRNA transfected groups, indicating cell proliferation isstimulated in cells with cell surface TCR and CD3. As expected,Cas9:TRAC sgRNA (targeting AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 76)), andCas9:CD3ε sgRNA (targeting GGGCACTCACTGGAGAGTTC (SEQ ID NO: 226))transfected cells did not exhibit cell proliferation after PHAtreatment, but exhibited strong proliferation after PMA/Ionomycintreatment. This result was consistent with our previous observation,Cas9:TRAC sgRNA and Cas9:CD3ε sgRNA treatment disrupts cell signalingthrough the TCR/CD3 complex.

Flow Cytometry Evaluation of CD107a and Intracellular Cytokines

Two other T cell activation events, degranulation and cytokineproduction, were also examined using flow cytometry. The transfectedcells were either untreated, PHA or PMA treated in serum and cytokinefree media. Concurrently, cells were incubated with Golgi Plug (BDBiosciences, San Jose, Calif.), Golgi Stop (BD Biosciences, San Jose,Calif.) and PE-Cy7 anti-human CD107a antibody (H4A3, Biolegend, SanDiego, Calif.). Four (4) hours post treatment, cells were surfacestained with the following antibodies anti-human CD3 (UCHT1, BioLegend,San Diego, Calif.), PE/Cy7 anti-human CD8 (SK1, BioLegend, San Diego,Calif.), and APC/Cy7 anti-human CD4 (RPA-T4, BioLegend, San Diego,Calif.) and fixed and permeabilized using BD Cytofix/Cytoperm Plus kit(BD Biosciences, San Jose, Calif.). Finally, cells were stained forintracellular cytokines with FITC anti-human TNFα antibody (Mab11,Biolegend, San Diego, Calif.), APC mouse anti-human IFNγ antibody(25723.11, BD Biosciences, San Jose, Calif.), and PE rat anti-human IL-2antibody (MQ1-17H12, BD Biosciences, San Jose, Calif.), washed, andanalyzed by flow cytometry.

Surface expressed CD107a is a marker for CD8+ T cell degranulationfollowing stimulation. Control cells that had received neither PHA norPMA/Ionomycin treatment showed minimal surface expression of CD107. BothPHA and PMA/Ionomycin treatments induced CD107a expression in mocktransfected, Cas9 alone, and Cas9:AAVS1 sgRNA transfected groups. Again,TCRα or CD3ε deficient cells showed base levels of CD107a expressionafter PHA treatment but largely increased levels of CD107a expressionafter PMA/Ionomycin treatment (FIG. 6B). This demonstrated thatPMA/Ionomycin, but not PHA, was able to induce degranulation in TCR/CD3deficient cells.

Similarly, enhanced levels of intracellular cytokine TNF, IFNγ, and IL-2were observed after either PHA or PMA/Ionomycin treatment in the mocktransfected, Cas9 alone, and Cas9:AAVS1 sgRNA transfected cells (FIG.6B).

Taken together, these experiments demonstrated that the TCR/CD3 complexis disrupted in the gene edited cells with signaling downstream of theTCR remaining intact in TCR/CD3 deficient cells, as indicated by cellproliferation, degranulation and effector cytokine production.

Example 4—Editing MHC II Components in Cells

This example demonstrates the in vitro functional consequences inprimary human T cells of editing MHC II components (CIITA or RFX5). Theresults are shown in FIG. 7.

Primary human T cells were transfected with RNP containing syntheticsgRNAs targeting AAVS1 (GGGGCCACTAGGGACAGGAT (SEQ ID NO: 1301)), B2M(GCTACTCTCTCTTTCTGGCC (SEQ ID NO: 417)), CIITA (GGTCCATCTGGTCATAGAAG(SEQ ID NO: 546)), RFX5-1 (TACCTCGGAGCCTCTGAAGA (SEQ ID NO: 1305)),RFX5-5 (TGTGCTCTTCCAGGTGGTTG (SEQ ID NO: 1306)), and RFX5-10(ATCAAAGCTCGAAGGCTTGG (SEQ ID NO: 1307)). 4-6 days post transfectioncells were treated with PMA/ionomycin overnight and surface levels ofMHC-II were assessed by flow cytometry (Tu39, PE-Cy7 conjugate,Biolegend). The amount of MHC-II induction (assessed by medianfluorescent intensity [MFI]) per test sample was normalized to theamount of MHC-II present on control (AAVS1) transfected cells (FIG. 7).The percentage of MHC-II+ cells remaining post transfection andPMA/ionomycin induction is indicated in the left panel. Data are from 4or 3 biological donors for single or dual sgRNA(s) transfected cells,respectively. Statistical significance was assessed using ANOVA withTukey post hoc correction.

In addition, RNPs containing Cas9 and sgRNAs targeting CIITA or RFX5diminish surface levels of MHC-II in induced primary human T cells.

The gRNAs used in this Example comprise the following spacer sequences:AAVS1 gRNA spacer (GGGGCCACUAGGGACAGGAU (SEQ ID NO: 1308)); B2M gRNAspacer (GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)); CIITA gRNA spacer(GGUCCAUCUGGUCAUAGAAG (SEQ ID NO: 738)), RFX5-1 gRNA spacer(UACCUCGGAGCCUCUGAAGA (SEQ ID NO: 1309)), RFX5-5 gRNA spacer(UGUGCUCUUCCAGGUGGUUG (SEQ ID NO: 1310)), and RFX5-10 gRNA spacer(AUCAAAGCUCGAAGGCUUGG (SEQ ID NO: 1311)).

Example 5—Editing Immune Checkpoint Components in Cells

Primary human T cells were transfected with RNP containing syntheticsgRNAs targeting PD-1 (CGCCCACGACACCAACCACC (SEQ ID NO: 916) andcomprising the spacer sequence of SEQ ID NO: 1108) or control. 4-6 dayspost transfection cells were treated with PMA/ionomycin, and surfacelevels of PD-1 were assessed by flow cytometry (EH12.2H7, BV421conjugate, Biolegend). The amount of PD1 induction (assessed by medianfluorescent intensity [MFI]) per test sample was normalized to theamount of PD1 present in untreated control transfected cells. Data arefrom 3 biological donors for single or dual sgRNA(s) transfected cells,respectively. Statistical significance was assessed using Student's ttest.

In addition, RNPs containing Cas9 and sgRNAs targeting PD1 diminishsurface levels of PD1 in induced primary human T cells.

Example 6—Multiplex Editing in Cells

This example demonstrates efficient multiplex editing and target proteinknock out in primary human T cells. The results are shown in FIG. 8.

Primary human T cells were transfected with RNP containing syntheticsgRNAs targeting the indicated genes. For the knockout of 2 or moregenes and their protein products in the same cell (multiplex editing), 1μM (final concentration) each of Cas9 pre-complexed individually withsgRNAs was added to the nucleofection mix. Surface levels of theindicated proteins were measured by flow cytometry 4-6 days aftertransfection. Antibodies used include BV510 anti-human CD3 (UCHT1,BioLegend, San Diego, Calif.), PE anti-human TCRαβ (BW242/412, MiltenyiBiotec, Auburn, Calif.), APC anti-human B2M (2M2, Biolegend), FITCanti-human CD52 (097, Biolegend). Each symbol is data from an individualbiological donor where test RNP treated cells are compared to controlRNP treated cells. Statistical significance was assessed by Student's ttest.

Guides used in this example are listed below with the respective targetand spacer sequences:

TRAC (SEQ ID NO: 76) AGAGCAACAGTGCTGTGGCC; (SEQ ID NO: 152)AGAGCAACAGUGCUGUGGCC B2M (SEQ ID NO: 417) GCTACTCTCTCTTTCTGGCC;(SEQ ID NO: 466) GCUACUCUCUCUUUCUGGCC CD3ε (SEQ ID NO: 226)GGGCACTCACTGGAGAGTTC; (SEQ ID NO: 351) GGGCACUCACUGGAGAGUUC; CD52(SEQ ID NO: 1303) TTACCTGTACCATAACCAGG (SEQ ID NO: 1312)UUACCUGUACCAUAACCAGG CIITA (SEQ ID NO: 546) GGTCCATCTGGTCATAGAAG(SEQ ID NO: 738) GGUCCAUCUGGUCAUAGAAG AAVS1 (SEQ ID NO: 1301)GGGGCCACTAGGGACAGGAT (SEQ ID NO: 1308) GGGGCCACUAGGGACAGGAU

In order to assess the feasibility of triple knockout using CRISPR/Cas9,primary T cells (5×10⁶) were transfected with pre-formed RNPs targetingthree separate genes: TRAC, B2M, and CIITA. RNP containing sgRNAstargeting AAVS1 served as a negative control. After 4 days, cells weresplit into two halves: one half was treated with anti-CD3/anti-B2Mbiotin antibodies and subsequently purified using StreptavidinMicrobeads (Miltenyi Biotec, Cambridge, Mass.), and the other halfremained untreated. Purified (pur) and unpurified (un) cells were bothanalyzed by TIDE. TIDE analysis showed that this approach produced atriple knockout InDel frequency of ˜36% compared to the control group,proving, at the DNA level, that it is possible to knockout three genessimultaneously using Cas9:sgRNA RNPs in a single experiment (FIG. 15).

In addition, the data in FIG. 15 demonstrates that efficient single,double, and triple gene knockout can be obtained in primary human Tcells transfected with Cas9:synthetic sgRNA (RNPs).

Example 7—HDR-Mediated Transgene Insertion in Cells

This example demonstrates efficient transgene insertion in primary humanT cells via homology directed repair (HDR) by Cas9:sgRNA RNP-mediateddouble-stranded genomic DNA breaks with an AAV6 donor DNA template.

Primary human T cells were isolated and activated with anti-CD3/CD28beads as described in Example 2. Beads were removed after 3 days. On day4, T cells (5×10⁶) were electroporated with Cas9 alone or Cas9:AAVS1sgRNA (targeting GGGGCCACTAGGGACAGGAT (SEQ ID NO: 1301)) RNP. 45 minpost transfection, 1×10⁶ of the Cas9 treated or the RNP treated cellswere either mock transduced (control), transduced with an AAV6-MND-GFPviral vector with AAVS1 homology arms with lengths of either 400 (HA400) or 700 (HA700) bp flanking the MND-GFP cassette (FIG. 10).Transduction with AAV6 was performed at an MOI of 50,000 viralgenomes/cell. As a negative control, cells were transfected with RNPcontaining sgRNA targeting the B2M gene (targeting GCTACTCTCTCTTTCTGGCC(SEQ ID NO: 417)). As the AAV6-MND-GFP virus does not contain homologyaround the B2M genomic cut sight, any integration observed in B2M RNPtreated cells would be the result of non-HDR mediated insertion. WhileGFP expression was observed after cutting with AAVS1, none was observedabove background with use of the B2M guide, indicating the absence ofnon-HDR mediated insertion.

To assess the efficiency of AAV6/RNP-mediated HDR, a PCR analysis (FIG.11) was performed. Forward and reverse primers flanking the RNP cutsites were used to amplify the region of 2.3 kb. PCR products wereseparated on an agarose gel. A band of 4 kb indicates an insertion ofthe MND-GFP sequence (1.7 kb) into the locus as a result of HDR. Only inthe presence of RNP targeting the AAVS1 locus was the 4 kb band evident,indicating successful insertion of the transgene by HDR. MND-GFPconstructs containing 700 bp of flanking homology arms to the AAVS1locus (HA700) appeared to lead to more efficient HDR than with homologyarms of 400 bp (HA400). These data demonstrate the feasibility ofperforming targeting transgene insertion into primary human T cells byCas9: sgRNA RNPs and AAV6 delivered donor DNA template. The gRNAs usedin this Example comprise the following spacer sequences: AAVS1 gRNAspacer (GGGGCCACUAGGGACAGGAU (SEQ ID NO: 1308)); and B2M gRNA spacer(GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)).

Example 8—HDR-Mediated Concurrent Transgene Insertion in Cells

This example demonstrates efficient transgene insertion and concurrentgene knockout by Cas9:sgRNA RNP (for double stranded break induction)and AAV6 delivered donor template to facilitate HDR in primary human Tcells.

Primary human T cells were activated with CD3/CD28 magnetic beads (asabove). Three days later activation beads were removed. The next day5×10⁶ cells were electroporated with RNP complexes with sgRNAs targetingeither AAVS1 (1 RNP), TRAC+B2M (2 separately complexed RNPs), orTRAC+B2M+AAVS1 (3 separately complexed RNPs). 1 hr post electroporation,cells were infected with −/+AAV6-MND-GFP viral vector with AAVS1homology arms with lengths of 700 bp flanking the MND-GFP cassette (AAV6(HA700-GFP) (FIG. 11). 7 days post manipulation cells were analyzed byflow cytometry by staining with the following antibodies PE anti-humanTCRαβ (BW242/412, Miltenyi Biotech, Auburn, Calif.), APC anti-human B2M(2M2, Biolegend), and GFP detection. Cells treated with RNPs targetingTRAC+ B2M showed loss of TRAC and B2M surface expression but no GFPexpression in either single or double knockout cells when infected withAAV6-HA700-GFP. When TRAC+ B2M treated cells are also electroporatedwith RNP targeting AAVS1 along with AAV6-HA700-GFP, GFP expression wasevident in both single knock-out and double knock-out cells, indicativeof HDR-mediated site specific insertion of the MND-GFP transgene.Finally, AAVS1 single RNP transfected cells showed high levels oftransgene expression, but no loss of TCR or B2M surface expression. Thesame experiment was repeated with activated T cells isolated from 3distinct biological donors (FIG. 12). The data show that high efficiencytransgene insertion by Cas9:sgRNA RNP induced double stranded break andsubsequent HDR from an AAV6 delivered DNA template (containing homologyto the cut site) can occur with concurrent knockout of up to 2 targetgenes with subsequent loss of surface protein expression at the singlecell level.

Guides used in this example target the following sequences:

(SEQ ID NO: 76) TRAC: AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 417) B2M:GCTACTCTCTCTTTCTGGCC (SEQ ID NO: 1301) AAVS1: GGGGCCACTAGGGACAGGAT

sgRNA sequences used herein: TRAC SEQ ID NO: 686, B2M SEQ ID NO: 688 andAAVS1 SEQ ID NO: 690, and can be modified as follows: TRAC SEQ ID NO:685, B2M SEQ ID NO: 687 and AAVS1 SEQ ID NO: 689. The gRNAs used in thisExample comprise the following spacer sequences: AAVS1 gRNA spacer(GGGGCCACUAGGGACAGGAU (SEQ ID NO: 1308)); TRAC gRNA spacer(AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152)); and B2M gRNA spacer(GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)).

Example 9—CRISPR/Cas9 Mediated Knockout of TCR and MHC I Components andExpression of Chimeric Antigen Receptor Constructs

This example describes the production by CRISPR/Cas9 and AAV6 ofallogeneic human T cells that lack expression of the TCR and MHC I andexpress a chimeric antigen receptor targeting CD19+ cancers.

Schematic depiction of CRISPR/Cas9 generated allogeneic CAR−T cells isshown in FIG. 13A and FIG. 13B.

CRISPR/Cas9 was used to disrupt (knockout [KO]) the coding sequence ofthe TCRa constant region gene (TRAC). This disruption leads to loss offunction of the TCR and renders the gene edited T cell non-alloreactiveand suitable for allogeneic transplantation, minimizing the risk ofgraft versus host disease. The DNA double stranded break at the TRAClocus was repaired by homology directed repair with an AAV6-deliveredDNA template containing right and left homology arms to the TRAC locusflanking a chimeric antigen receptor cassette (−/+ regulatory elementsfor gene expression). To reduce host versus graft (host vs CAR−T) andallow for persistence of the allogeneic CAR−T product, the B2M gene wasdisrupted by CRISPR/Cas9 components. Together, these genome edits resultin a T cell with surface expression of a CAR (expressed from the TRAClocus) targeting CD19+ cancers along with loss of the TCR and MHC I, toreduce GVH and HVG disease, respectively.

Schematics of the AAV vector genome carrying donor templates tofacilitate targeted genomic insertion of CAR expression cassettes by HDRof Cas9-evoked site specific DNA double stranded breaks are shown inFIG. 14.

TABLE 12 Donor Template Component Sequences SEQ ID Length NO: SequenceDomain Name ( bp) 1313 TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGLeft ITR (5′ ITR) 145 GCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGG GAGTGGCCAACTCCATCACTAGGGGTTCCT1576 CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCG Left ITR (5′ ITR) 130CCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTG (alternate)AGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCAT CACTAGGGGTTCCT 1314AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGC Right ITR (3′ 145GCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCC ITR)GGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGC GAGCGAGCGCGCAGAGAGGGAGTGGCCAA1577 AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGC Right ITR (3′ 141GCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTC ITR)(alternate)GCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAG CGAGCGAGCGCGCAGCTGCCTGCAGG 1315GGCCGCCAGTGTGATGGATATCTGCAGAATTCGCCCTTA pMND 451TGGGGATCCGAACAGAGAGACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGTTGGAACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGATGGTCCCCAGATGCGGTCCCGCCCTCAGCAGTTTCTAGAGAACCATCAGATGTTTCCAGGGTGCCCCAAGGACCTGAAATGACCCTGTGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCGCGCTTCTGCTCCCCGAGCTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCT CCATAGAAGACACCGACTCTAGAG 1316ATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTC FMC63-28Z 1518CTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGA (FMC63-CTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACC CD8[tm]-GAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGC CD28[co-AAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAAC stimulatoryGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTC domain]-CD3z)CGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCC TGCCTCCCAGA 1317GGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGC 2A 66TGGAGACGTGGAGGAGAACCCTGGACCT 1318 ATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTEGFP 720 GCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCA CTCTCGGCATGGACGAGCTGTACAAGTAA1319 AATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGT pA 49 TTTTTGTGTG 1320GAAGCCCAGAGCAGGGCCTTAGGGAAGCGGGACCCTGC AAVS1-LHA 700TCTGGGCGGAGGAATATGTCCCAGATAGCACTGGGGACTCTTTAAGGAAAGAAGGATGGAGAAAGAGAAAGGGAGTAGAGGCGGCCACGACCTGGTGAACACCTAGGACGCACCATTCTCACAAAGGGAGTTTTCCACACGGACACCCCCCTCCTCACCACAGCCCTGCCAGGACGGGGCTGGCTACTGGCCTTATCTCACAGGTAAAACTGACGCACGGAGGAACAATATAAATTGGGGACTAGAAAGGTGAAGAGCCAAAGTTAGAACTCAGGACCAACTTATTCTGATTTTGTTTTTCCAAACTGCTTCTCCTCTTGGGAAGTGTAAGGAAGCTGCAGCACCAGGATCAGTGAAACGCACCAGACGGCCGCGTCAGAGCAGCTCAGGTTCTGGGAGAGGGTAGCGCAGGGTGGCCACTGAGAACCGGGCAGGTCACGCATCCCCCCCTTCCCTCCCACCCCCTGCCAAGCTCTCCCTCCCAGGATCCTCTCTGGCTCCATCGTAAGCAAACCTTAGAGGTTCTGGCAAGGAGAGAGATGGCTCCAGGAAATGGGGGTGTGTCACCAGATAAGGAATCTGCCTAACAGGAGGTGGGGGTTAGACCCAATATCAGGAGACTAGGAAGGAGGAGGCCTAAGGATGGGGCT TTTCTGTCACCA 1321ACTGTGGGGTGGAGGGGACAGATAAAAGTACCCAGAAC AAVS1-RHA 700CAGAGCCACATTAACCGGCCCTGGGAATATAAGGTGGTCCCAGCTCGGGGACACAGGATCCCTGGAGGCAGCAAACATGCTGTCCTGAAGTGGACATAGGGGCCCGGGTTGGAGGAAGAAGACTAGCTGAGCTCTCGGACCCCTGGAAGATGCCATGACAGGGGGCTGGAAGAGCTAGCACAGACTAGAGAGGTAAGGGGGGTAGGGGAGCTGCCCAAATGAAAGGAGTGAGAGGTGACCCGAATCCACAGGAGAACGGGGTGTCCAGGCAAAGAAAGCAAGAGGATGGAGAGGTGGCTAAAGCCAGGGAGACGGGGTACTTTGGGGTTGTCCAGAAAAACGGTGATGATGCAGGCCTACAAGAAGGGGAGGCGGGACGCAAGGGAGACATCCGTCGGAGAAGGCCATCCTAAGAAACGAGAGATGGCACAGGCCCCAGAAGGAGAAGGAAAAGGGAACCCAGCGAGTGAAGACGGCATGGGGTTGGGTGAGGGAGGAGAGATGCCCGGAGAGGACCCAGACACGGGGAGGATCCGCTCAGAGGACATCACGTGGTGCAGCGCCGAGAAGGAAGTGCTCCGGAAAGAGCATCCTTGGGCAGCAACACAGCAGAGAGCAAGGGGAAGAGGGAGTGGAGGAAG ACGGAACCTGAAGGAGGCGGC 1322GAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTA TRAC-LHA 500AGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCA (500 bp)GGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCA 1323TGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTC TRAC-RHA 500AACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGC (500 bp)CCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCC 1324GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTAT TRAC-LHA 678ATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTG (680 bp)TTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAG CTGAGAGACTCTAAATC 1325GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTAT TRAC-LHA 800ATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTG (800 bp)TTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTA GACATGAGGTCTATGGACTTCA 1326TGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTC TRAC-RHA 804AACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGC (800 bp)CCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAG AGGCCTGGGACAGGAGCTCAATGAGAAAGG1327 TAATCCTCCGGCAAACCTCTGTTTCCTCCTCAAAAGGCA TRAC-LHA 1000GGAGGTCGGAAAGAATAAACAATGAGAGTCACATTAAA (1000 bp)AACACAAAATCCTACGGAAATACTGAAGAATGAGTCTCAGCACTAAGGAAAAGCCTCCAGCAGCTCCTGCTTTCTGAGGGTGAAGGATAGACGCTGTGGCTCTGCATGACTCACTAGCACTCTATCACGGCCATATTCTGGCAGGGTCAGTGGCTCCAACTAACATTTGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATGGAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGGAAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTC CTAACCCTGATCCTCTTGTCCCACAGATATC1328 CCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATT TRAC-RHA 999CTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGT (1000 bp)ATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGAGAAGAGCAGCAGGCATGAG TTGAATGAAGGAGGCAGGGCCGGGTCACAGGG1578 TGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATG TRAC-LHA used 800GAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGG in CTX-139.1AAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTAC CAGCTGAGAGACTCTAAATC 1579TGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATG TRAC-LHA usedGAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGG in CTX-139.2AAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGC C 1580TGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTC TRAC-RHAAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGC used in CTX-CCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTC 139.2CTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAG AGGCCTGGGACAGGAGCTCAATGAGAAAGG1581 TGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATG TRAC-LHA (841GAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGG bp) used in CTX-AAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAAT 139.3TCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGA CTATTCACCGATTTTGATTCTC 1582ATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAG TRAC-RHATAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCT (905  bp) used inAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTG CTX-139.3TGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTA TAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG1329 TTTTGTAAAGAATATAGGTAAAAAGTGGCATTTTTTCTT CD3E-LHA 700TGGATTTAATTCTTATGGATTTAAGTCAACATGTATTTTC (700 bp)AAGCCAACAAGTTTTGTTAATAAGATGGCTGCACCCTGCTGCTCCATGCCAGATCCACCACACAGAAAGCAAATGTTCAGTGCATCTCCCTCTTCCTGTCAGAGCTTATAGAGGAAGGAAGACCCCGCAATGTGGAGGCATATTGTATTACAATTACTTTTAATGGCAAAAACTGCAGTTACTTTTGTGCCAACCTACTACATGGTCTGGACAGCTAAATGTCATGTATTTTTCATGGCCCCTCCAGGTATTGTCAGAGTCCTCTTGTTTGGCCTTCTAGGAAGGCTGTGGGACCCAGCTTTCTTCAACCAGTCCAGGTGGAGGCCTCTGCCTTGAACGTTTCCAAGTGAGGTAAAACCCGCAGGCCCAGAGGCCTCTCTACTTCCTGTGTGGGGTTCAGAAACCCTCCTCCCCTCCCAGCCTCAGGTGCCTGCTTCAGAAAATGGTGAGTCTCTCTCTTATAAAGCCCTCCTTTTTCATCCTAGCATTGGGAACAATGGCCCCAGGGTCCTTATCTCTAGCAGATGTTTTGAAAAAGTCATCTGTTTTGCTTTTTTTCCAGAAGTAGTAAGTCTGCTGGCCTCCGCCATCTTAGTAAAGTAACAGTCCCATGAAACAAAG 1330GTGAGTAGGATGGAGTGGAAAGGGTGGTGTGTCTCCAG CD3E-RHA 700ACCGCTGGAAGGCTTACAGCCTTACCTGGCACTGCCTAG (700 bp)TGGCACCAAGGAGCCTCATTTACCAGATGTAAGGAACTGTTTGTGCTATGTTAGGGTGAGGGATTAGAGCTGGGGACTAAAGAAAAAGATAGGCCACGGGTGCCTGGGAGAGCGTTCGGGGAGCAGGCAAAGAAGAGCAGTTGGGGTGATCATAGCTATTGTGAGCAGAGAGGTCTCGCTACCTCTAAGTACGAGCTCATTCCAACTTACCCAGCCCTCCAGAACTAACCCAAAAGAGACTGGAAGAGCGAAGCTCCACTCCTTGTTTTGAAGAGACCAGATACTTGCGTCCAAACTCTGCACAGGGCATATATAGCAATTCACTATCTTTGAGACCATAAAACGCCTCGTAATTTTTAGTCCTTTTCAAGTGACCAACAACTTTCAGTTTATTTCATTTTTTTGAAGCAAGATGGATTATGAATTGATAAATAACCAAGAGCATTTCTGTATCTCATATGAGATAAATAATACCAAAAAAAGTTGCCATTTATTGTCAGATACTGTGTAAAGAAAAAATTATTTAGACGTGTTAACTGGTTTAATCCTACTTCTGCCTAGGAAGGAAGGTGTTATATCCTCTTTTTAAAATTCTTTTTAATTTTGACTATATAAACTGATA A 1331GGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCC EF1a 1178CACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCC ATTTCAGGTGTCGTGAFMC63-28Z (FMC63-CD8[tm]-CD28[co-stimulatory domain]-CD3z) Component Sequences1332 ATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTC GM-CSF signalCTCATCCAGCGTTCTTGCTGATCCCC peptide 1598 MLLLVTSLLLCELPHPAFLLIPGM-CSF signal peptide 1333 GATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCAnti-CD19 scFv TCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGT 1334DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPD CD19 scFvGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDI amino acidATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTK sequenceGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQP LinkerPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLK underlinedMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVS S 1335GCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCG CD8aACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCC transmembrane +ACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCA 5′ LinkerTGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGG (underlined)CTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATT ACTTTGTATTGTAATCACAGGAATCGC 1599TTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACT CD8aCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCC transmembraneTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCC (without linker)GCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATT GTAATCACAGGAATCGC 1600FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAG CD8aGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHR transmembrane NR 1336TCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAAT CD28 co-ATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTA stimulatoryCCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAG GTCC 1601SKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS CD28 co- stimulatory 1337CGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATAT CD3zCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACG ATGCACTGCATATGCAGGCCCTGCCTCCCAGA1602 RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRR CD3z peptideGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 1338MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVT FMC63-28ZISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSR (FMC63-FSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGT CD8[tm]-KLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSL CD28[co-SVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY stimulatoryYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKH domain]-CD3z)YYYGGSYAMDYWGQGTSVTVSSAAAFVPVFLPAKPTTTP Amino AcidAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI CD8aYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYM transmembraneNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPA underlinedYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR

CTX-131 (SEQ ID NO: 1348) contains a CAR(FMC63-CD8[tm]-CD28[co-stimulatory domain]-CD3z) construct (SEQ ID NO:1316) with a synthetic 3′ poly adenylation sequence (pA) whoseexpression is driven by the MND promoter and is translationally linkedby a picornavirus 2A sequence to any potential downstream transcript(GFP is shown in this example). CTX-131 contains homology arms flankinga genomic Cas9/sgRNA target site in the AAVS1 locus. CTX-132 (SEQ ID NO:1349) is the same version of this construct, but lacking homology armsto AAVS1.

CTX-133 (SEQ ID NO: 1350) contains a CAR(FMC63-CD8[tm]-CD28[co-stimulatory domain]-CD3z) construct (SEQ ID NO:1316) with a synthetic 3′ poly adenylation sequence (pA) whoseexpression is driven by the EF1a promoter and is translationally linkedby a picornavirus 2A sequence to any potential downstream transcript(GFP is shown in this example). CTX-133 contains homology arms flankinga genomic Cas9/sgRNA target site in the TRAC locus. CTX-134 (SEQ ID NO:1351) is the same version of this construct, but lacking homology armsto TRAC. CTX-138 (SEQ ID NO: 1354) is a version of CTX-133 lacking the2A-GFP sequence, and the 500 bp flanking homology arms are replaced with800 bp flanking homology arms. CTX-139 (SEQ ID NO: 1355) is a version ofCTX-138 where the TRAC left homology arm was replaced with a 678 bphomology arm (TRAC−LHA (680 bp)).

CTX-140 (SEQ ID NO: 1356) contains a CAR(FMC63-CD8[tm]-CD28[co-stimulatory domain]-CD3z) construct (SEQ ID NO:1316) with a synthetic 3′ poly adenylation sequence (pA) whoseexpression is driven by endogenous TCR regulatory elements and istranslationally linked by a picornavirus 2A sequence to any potentialupstream TCRa transcript. CTX-140 contains homology arms flanking agenomic Cas9/sgRNA target site in the TRAC locus (distinct from CTX-133,CTX-138, and CTX-139). CTX-141 (SEQ ID NO: 1357) is the same version ofthe CTX-140 construct and is also translationally linked to anypotential downstream sequence by an additional 2A sequence (GFP is shownin this example).

CTX-139.1 construct (SEQ ID NO: 1583) is a similar version of theCTX-139 construct however the left homology arm (LHA) sequence isreplaced with an alternate 800 bp TRAC−LHA, creating a larger deletionupon homologous recombination. CTX-139.2 is similar to CTX139.1 but withan extended 20 bp LHA and 105 bp RHA that brings homologous sequencecloser to the Exon1_T7 guide cut site but is missing the Exon1_T7 guidetarget sequence. CTX-139.3 is similar to CTX-139.2 with an additional 21bp added to the LHA and 20 bp added to the RHA. CTX-139.2 contains allthe Exon1_T7 guide target sequence but has a mutation in thecorresponding PAM sequence.

CTX-135 (SEQ ID NO: 1352) contains a CAR(FMC63-CD8[tm]-CD28[co-stimulatory domain]-CD3z) construct (SEQ ID NO:1316) with a synthetic 3′ poly adenylation sequence (pA) whoseexpression is driven by endogenous CD3E regulator elements and istranslationally linked by a picornavirus 2A sequence to any potentialdownstream transcript (GFP is shown in this example). CTX-135 contains700 bp homology arms flanking a genomic Cas9/sgRNA target site in theCD3E locus. CTX-136 (SEQ ID NO: 1353) is a version of CTX-135 butlacking homology arms to CD3E.

CRISPR/Cas9 Mediated Knockout of TCR and MHC I Components, Expression ofChimeric Antigen Receptor (CAR) Constructs, and Retained EffectorFunction

This example describes the production by CRISPR/Cas9 and AAV6 ofallogeneic human T cells that lack expression of TCR and MHC I, thatexpress a chimeric antigen receptor targeting CD19+ cancers, and thatretain T cell effector function.

Transgene insertion in primary human T cells via homology directedrepair (HDR) and concurrent gene knockout by Cas9:sgRNA RNA wasperformed as described above in Examples 8 and 9. Primary human T cellswere first electroporated with Cas9 or Cas9:sgRNA RNP complexestargeting TRAC (AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 76)),B2M⁻/(GCTACTCTCTCTTTCTGGCC (SEQ ID NO: 417)), or AAVS1(GGGGCCACTAGGGACAGGAT (SEQ ID NO: 1301)). The gRNAs used in this Examplecomprise the following spacer sequences: AAVS1 gRNA spacer(GGGGCCACUAGGGACAGGAU (SEQ ID NO: 1308)); TRAC gRNA spacer(AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152)); and B2M gRNA spacer(GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)).

T cell staining was performed as described above in Example 3 with amodification in which the cells were stained with anti-mouse Fab₂antibody labeled with biotin (115-065-006, Jackson ImmunoRes) at adilution of 1:5 for 30 minutes at 4° C. The cells were then washed andstained with a streptavidin conjugate. The flow cytometry results areshown in FIGS. 17A & 17B.

The ability of the engineered cells to lyse Raji lymphoma cells and toproduce interferon gamma (IFNg or IFNγ) was then analyzed using a cellkill assay and ELISA. Briefly, the cell kill assay and ELISA wereperformed using black walled 96 well plates, 100 ug Staurosporine(Fisher 1285100U), Cell Stimulation Cocktail (PMA) (Fisher 501129036),Trypan Blue (Fisher 15250061), PBS, and Raji media (10% Heat-InactivatedFetal Bovine Serum (Sigma F4135-500ML, 15L115)) and RPMI 1640 (LifeTechnologies 61870036)) or K562 Media (10% Heat-Inactivated Fetal BovineSerum (Sigma F4135-500ML, 15L115) and IMDM (Life Technologies 12440061).

T-cells and CAR−T samples were re-suspended in the appropriate RPMI/10%FBS to a dilution of 4.0×10⁵/100 μL, and Luciferase expressing cellswere re-suspended at 1.0×10⁵/100 uL. After re-suspension, all sampleswere plated at a final volume of 200 uL per well as shown. Plates wereincubated overnight, and after 24 hours, plates were spun down for 10minutes. Thirty (30) μL of the top supernatant media was collected foruse in the IFNγ ELISA (RD Systems SIF50) on a new plate. The remainingplate volume was then used in the Luciferase Assay (Perkin Elmer6RT0665).

T cells expressing an anti-CD19 CAR construct either from the AAVS1locus (AAVS1 RNP+CTX-131) or from the TRAC locus (TRAC RNP+CTX-138) wereable to lyse the Raji lymphoma cells in a coculture assay (FIG. 16A,left panel). The CAR−T cells, but not CAR negative controls, were ableto produce Interferon gamma (IFNγ or IFNg) in the presence of Rajilymphoma cells (FIG. 16A, right panel). Anti-CD19 CAR−T cells generatedby CRISPR/AAV did not produce IFNγ when cocultured with K562 cells, acell line negative for CD19 expression. When K562 were produced tooverexpress CD19, and cocultured with CAR−T cells expressing anti-CD19CAR from either from the AAVS1 locus (AAVS1 RNP+CTX-131) or from theTRAC locus (TRAC RNP+CTX-138), the CAR−T expressing cells induced IFNγproduction. FIG. 16B (left panel) show that CAR−T cells expressinganti-CD19 CAR do not induce IFNγ in K562 cells lacking CD19. However,IFNγ levels of CAR−T cells expressing anti-CD19 CAR are stimulated inK562 cells expressing CD19 (FIG. 16B, right panel).

FIG. 17A demonstrates that single cells engineered to express a CARconstruct and to lack surface expression of TCR and B2M did so only whenthe cells were treated with RNPs to TRAC and B2M and infected with AAV6(CTX-138) that delivers a donor template containing a CAR constructflanked by homologous sequence to the TRAC locus mediated site specificintegration and expression of the CAR construct. Normal proportions ofCD4 and CD8 T cells that were CAR⁺TCR⁻B2M⁻ were observed, as shown inFIG. 17B and FIG. 17C. The engineered cells remained viable 8 days postelectroporation and AAV6 infection, as shown in FIG. 17D.

FIGS. 18A and 18B demonstrate that the engineered cells produced andincreased level of production of interferon gamma (IFNg or IFNγ) only incells made to express an anti-CD19 CAR integrated in the TRAC locus withor without knockout of B2M when T cells were cocultured withCD19-expressing K562 cells. FIG. 18C demonstrates increased IFNγproduction in co-cultures of CD19+ Raji lymphoma cell line and T cellstreated as indicated.

CAR Expression Using rAAV Constructs with Different TRAC sgRNAs

This example describes the effect of donor design and guide selection onCAR expression in allogeneic human T cells that lack expression of TCRand MHC I, and express a chimeric antigen receptor. Cells were preparedusing the following sgRNAs: TRAC gRNA spacer “EXON1_T32”:AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152); sgRNA (SEQ ID NO: 1345); TRACgRNA spacer “Exon1_T7” (GAGAAUCAAAAUCGGUGAAU (SEQ ID NO: 88); sgRNA (SEQID NO: 1588), and rAAV constructs show in the table below.

The homology arms used in AAV constructs can be designed to moreefficiently pair with gRNAs and/or induce a deletion or mutation in thetargeted gene locus (e.g.: TRAC locus) following transgene insertion.For example, the homology arms can be designed to flank one or morespacer sequences that results in the deletion of the spacer sequence(s)following transgene insertion by HDR (e.g.: CTX-138). Alternatively,homology arms can be designed with alterations in the TRAC sequence thatresult in base pair changes, generating mutations in the PAM or spacersequences. Specific guide design, paired with a particular guide RNA canimprove CAR expression.

TABLE 12.1 Construct design and effect of transgene insertion on TRACgene Donor template LHA RHA (LHA- SEQ ID LHA SEQ ID RHA SEQ ID RHA) NO:(bp) NO: (bp) NO: CTX-138 1354 800 1325 800 1326 CTX-139 1355 678 1324800 1326 CTX-139.1 1583 800 1578 800 1326 CTX-139.2 1584 820 1579 9051580 CTX-139.3 1585 841 1581 925 1582

TABLE 12.1A CAR expression following transgene insertion Donor templateGuide: Guide: (LHA- Effect of HDR on EXON1_T32 EXON1_T7 RHA) TRAC locusSEQ ID NO: SEQ ID NO: CTX-138 20 bp deletion spanning 55% 9.5% Exon1_T32target sequence CTX-139 141 bp deletion spanning 54%  30% Exon1_T32 &Exon1_T7 target sequence CTX-139.1 141 bp deletion spanning n.a.  19%Exon1_T32 & Exon1_T7 target sequence CTX-139.2 20 bp deletion spanningn.a.  50% Exon1_T7 target sequence CTX-139.3 0 bp deletion; mutates PAMn.a.  54% sequence 3′ of Exon1_T7 target sequence; (1 nucleotide changein PAM)

Example 10—Analysis of On-Target Indel Profiles in T Cells

On-target amplicon analysis was conducted the TRAC and B2M locusfollowing gene editing using the following guides:

B2M spacer: (SEQ ID NO: 466)GCUACUCUCUCUUUCUGGCC; sgRNA (SEQ ID NO: 1343 TRAC spacer:(SEQ ID NO: 152) AGAGCAACAGUGCUGUGGCC; sgRNA (SEQ ID NO: 1345)

Following gene editing, on-target amplicon analysis was conducted aroundthe TRAC and B2M locus in TRAC−/B2M−/anti-CD19 CAR+ cells.

An initial PCR was performed using the 2× Kapa HiFi Hotstart Mastermix(Kapa Biosystems, Wilmington, Mass.). 50 ng of input gDNA was combinedwith 300 nM of each primer. The TRAC_F and TRAC_R primers were pairedfor the TRAC locus, and the B2M_F and B2M_R primers were paired toamplify the B2M locus (Table ##).

TABLE 12.2 Primers for TRAC and B2M amplicon library preparation TRAC_FTCGTCGGCAGCGTCAGATGTGTATAAGAGACAG cgtgtaccagctgagagact TRAC_RGTCTCGTGGGCTCGGAGATGTGTATAAGAGACAG atgctgttgttgaaggcgtt B2M_FTCGTCGGCAGCGTCAGATGTGTATAAGAGACAG gggcattcctgaagctgaca B2M_RGTCTCGTGGGCTCGGAGATGTGTATAAGAGACAG ttggagaagggaagtcacgg

Analysis of the B2M locus in a population of T cells following geneediting to produce TRAC⁻/B2M⁻/CAR+ T cells results in the followingindel frequencies and edited gene sequences at the B2M locus (deletionsas dashes and insertions in bold).

TABLE 12.3 SEQ ID NO: Gene edited sequence Frequency 1560CGTGGCCTTAGCTGTGCTCGCGCTACTCTCTCTTTCT- 16.2%GCCTGGAGGCTATCCAGCGTGAGTCTCTCCTACCCTCC CGCT 1561CGTGGCCTTAGCTGTGCTCGCGCTACTCTCTCTTTC-- 6.3%GCCTGGAGGCTATCCAGCGTGAGTCTCTCCTACCCTC CCGCT 1562CGTGGCCTTAGCTGTGCTCGCGCTACTCTCTCTTT----- 4.7%CTGGAGGCTATCCAGCGTGAGTCTCTCCTACCCTCCC GCT 1563CGTGGCCTTAGCTGTGCTCGCGCTACTCTCTCTTTCTG 2.2%GATAGCCTGGAGGCTATCCAGCGTGAGTCTCTCCTAC CCTCCCGCT 1564CGTGGCCTTAGCTGTGCTCGC------------------------- 2.1%GCTATCCAGCGTGAGTCTCTCCTACCCTCCCGCT 1565CGTGGCCTTAGCTGTGCTCGCGCTACTCTCTCTTTCTG 2.1%TGGCCTGGAGGCTATCCAGCGTGAGTCTCTCCTACCC TCCCGCT

Analysis of the TRAC locus in a population of T cells following geneediting to produce TRAC⁻/B2M⁻/CAR+ T cells results in the followingindel frequencies and edited gene sequences at the TRAC locus in T cellswithout a CAR insertion (deletions as dashes and insertions in bold).

TABLE 12.4 SEQ ID NO: Gene edited sequence Frequency 1566AA---------------------GAGCAACAAATCTGACT 16.4% 1567 AAGAGCAACAGTGCTGT-16.0% GCCTGGAGCAACAAATCTGACT 1568AAGAGCAACAGTG-------CTGGAGCAACAAATCTGACT 7.5% 1569 AAGAGCAACAGT------7.0% GCCTGGAGCAACAAATCTGACT 1570AAGAGCAACAGTG---------------------CTGACT 1.6% 1571AAGAGCAACAGTGCTGTGGGCCTGGAGCAACAAATC 2.5% TGACT 1572 AAGAGCAACAGTGC--2.2% TGGCCTGGAGCAACAAATCTGACT 1573 AAGAGCAACAGTGCTGTGTGCCTGGAGCAACAAATC2.0% TGACT

Example 11—Production of Site-Specific Allogeneic CD19 CAR−T Cells byCRISPR-Cas9 for B-Cell Malignancies

CRISPR/Cas9 technologies have been applied to develop anti CD19allogeneic chimeric antigen receptor T cells (CAR−T) with reducedpotential for graft vs. host disease (GVHD), and reduced rejectionpotential for the treatment of CD19 positive malignancies. Theefficiency of the CRISPR/Cas9 system enables rapid production ofhomogeneous CAR−T product from prescreened healthy donors and thus canpotentially be developed as an “off-the-shelf” therapy for efficientdelivery to patients. Autologous CAR−T therapeutics targeting CD19 haveshown impressive responses in B-cell malignancies but currently requiresignificant individualized manufacturing efforts and can suffer frommanufacturing failures. In addition, these autologous CAR−Ts areproduced using retrovirus or lentivirus, for which the variable natureof integration can lead to a heterogeneous product. Allogeneic or“off-the-shelf” CAR−T products with site-specific CAR integrationgenerated with gene editing technologies may address some of thesesignificant challenges seen for autologous products.

CRISPR-Cas9 technology was utilized in primary human T cells to produceallogeneic CAR−T cells by multiplexed genome editing. A robust systemfor site-specific integration of CAR and concurrent multiplexed geneediting in single T cells has been developed by utilizinghomology-directed repair (HDR) with Cas9 ribonucleoprotein (RNP) and anAAV6-delivered donor template.

With CRISPR/Cas9 editing technology, high frequency knockout of theconstant region of the TCRα gene (TRAC) with ˜98% reduction of TCRsurface expression in human primary T-cells from healthy donors, whichaims to significantly impair graft-versus-host disease (GVHD), wasachieved. High frequency knockout of the β-2-microglobulin (B2M) genecould also be obtained, which aims to increase persistence in patients,potentially leading to increased potency overall. TRAC/B2M doubleknockout frequencies have been obtained in ˜80% of T cells without anysubsequent antibody-based purification or enrichment. Human T cellsexpressing a CD19-specific CAR from within a disrupted TRAC locus,produced by homology-directed repair using an AAV6-delivered donortemplate, along with knockout of the B2M gene have been consistentlyproduced at a high efficiency. This site-specific integration of the CARprotects against the potential outgrowth of CD3⁺CAR⁺ cells, furtherreducing the risk of GVHD, while also reducing the risk of insertionalmutagenesis associated with retroviral or lentiviral deliverymechanisms. These engineered allogeneic CAR−T cells show CD19-dependentT-cell cytokine secretion and potent CD19-specific cancer cell lysis.

We are able to use genome editing with the CRISPR-Cas9 system toefficiently create an allogeneic or “off-the-shelf” CAR−T cell product(e.g.: TC1) that demonstrates potent and specific anticancer effects forpatients with CD19-expressing human cancers. More specifically, and asdemonstrated herein the production of allogeneic anti-CD19 CAR−T product(FIG. 40) that exhibits high efficiency editing (e.g., greater than 50%TRAC⁻/B2M⁻/anti-CD19CAR+T cells efficiency) (FIG. 39), CD19-specificeffector functions (FIG. 35 and FIG. 41), kills CD19⁺ leukemia orlymphoma cells in vitro and in vivo (FIG. 35 and FIG. 42), and does notproliferate in the absence of cytokines (FIG. 23). In addition, theoff-target profile is consistent with results from other gene-edited Tcell therapeutics in development.

Example 12—Dose Escalation Study to Determine the Efficacy of CAR−TCells in the Subcutaneous Raji Human Burkett's Lymphoma Tumor XenograftModel in NOG Mice

In this example, the efficacy of CAR−T cells against the subcutaneousRaji Human Burkett's Lymphoma tumor xenograft model in NOG mice wasevaluated. Transgene insertion in primary human T cells via homologydirected repair (HDR) and concurrent gene knockout by Cas9:sgRNA RNA wasperformed as described above in Examples 8-10 to produce cells lackingTCR and B2M surface expression and to concurrently express an anti-CD19CAR construct (TRAC⁻/B2M⁻CD19CAR+ cells). Primary human T cells werefirst electroporated with Cas9 or Cas9:sgRNA RNP complexes targetingTRAC (AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 76) and B2M1(GCTACTCTCTCTTTCTGGCC (SEQ ID NO: 417)). The DNA double stranded breakat the TRAC locus was repaired by homology directed repair with anAAV6-delivered DNA template (CTX-138; SEQ ID NO: 675) containing rightand left homology arms to the TRAC locus flanking a chimeric antigenreceptor cassette (−/+ regulatory elements for gene expression). Theresulting modified T cells (TC1) are TRAC⁻/B2M⁻CD19CAR+. The ability ofthe modified TRAC⁻/B2M⁻CD19CAR+ T cells to ameleriote disease caused bya CD19+ lymphoma cell line (Raji) was evaluated in NOG mice usingmethods employed by Translational Drug Development, LLC (Scottsdale,Ariz.). In brief, 12, 5-8 week old female, CIEA NOG(NOD.Cg-Prkdc^(scid)I12rg^(tm1Sug)/JicTac) mice were individually housedin ventilated microisolator cages, maintained under pathogen-freeconditions, 5-7 days prior to the start of the study. On Day 1 micereceived a subcutaneous inoculation of 5×10⁶ Raji cells/mouse. The micewere further divided into 3 treatment groups as shown in Table 13. OnDay 8 (7 days post inoculation with the Raji cells), treatment group 2and group 3 received a single 200 μl intravenous dose ofTRAC⁻/B2M⁻CD19CAR+ cells (TC1) according to Table 13. The gRNAs used inthis Example comprise the following spacer sequences:

TRAC gRNA spacer (SEQ ID NO: 152) (AGAGCAACAGUGCUGUGGCC); andB2M gRNA spacer (SEQ ID NO: 466) (GCUACUCUCUCUUUCUGGCC).

TABLE 13 Treatment groups Group Raji Cells (s.c.) TC1 Treatment (i.v.) N1 5 × 10⁶ cells/mouse None 4 2 5 × 10⁶ cells/mouse 5 × 10⁶ cells/mouse 43 5 × 10⁶ cells/mouse 1 × 10⁷ cells/mouse 4

Tumor volume and body weight was measured and individual mice wereeuthanized when tumor volume was ≥500 mm³.

By Day 18, the data show a statistically significant decrease in thetumor volume in response to TC1 cells as compared to untreated mice(FIG. 19). The effect on tumor volume was dose-dependent (Table 14);mice receiving higher doses of TC1 cells showed significantly reducedtumor volume when compared to mice receiving either a lower dose of TC1cells or no treatment. An increase in survival was also observed in thetreated group (Table 14).

TABLE 14 Tumor response and survival Tumor volume Tumor volume SurvivalGroup (Day 18) (Day 20) (Days) N 1 379.6 ± 67.10   482 ± 47.37 20-22 4 2214.0 ± 20.73 372.2 ± 78.21 25 4 3 107.5 ± 7.33* 157.1 ± 10.62** 27 (endof study) 4 p = 0.007 compared to control (Group 1) **p = 0.0005compared to control (Group 1)

In addition to CT1 described above, additional modified T cellsexpressing a chimeric antigen receptor (CAR) comprising an extracellulardomain comprising an anti-CD19 scFv and further comprising a doubleknock-out of the TRAC and B2M genes are contemplated for use this andother examples described herein. In certain embodiments the TRAC⁻/B2M⁻CD19CAR+ cells, the TRAC deletion may be accomplished using any one ofthe TRAC spacer sequences described herein. In certain embodiments ofthe TRAC⁻/B2M⁻CD19CAR+ cells, the β2M deletion may be accomplished usingany one of the B2M spacer sequences described herein.

Example 13—Assessment of CAR−T Cells Efficacy in IntravenousDisseminated Models in NOG Mice

Intravenous Disseminated Raji Human Burkett's Lymphoma Tumor XenograftModel

The Intravenous Disseminated Model (Disseminated Model) using the RajiHuman Burkett's Lymphoma tumor cell line in NOG mice was used in thisexample to further demonstrate the efficacy of TRAC⁻/B2M⁻CD19CAR+ cells.Generation of the TRAC⁻/B2M⁻CD19CAR+ cells (TC1) used in this model wasdescribed in the Examples above and evaluated in the Disseminated Modelusing methods employed by Translations Drug Development, LLC(Scottsdale, Ariz.) and described herein. In brief, 24, 5-8 week oldfemale CIEA NOG (NOD.Cg-Prkdc^(scid)I12rg^(tm1Sug)/JicTac) mice wereindividually housed in ventilated microisolator cages, maintained underpathogen-free conditions, 5-7 days prior to the start of the study. Atthe start of the study, the mice were divided into 5 treatment groups asshown in Table 15. On Day 1 mice in Groups 2-5 received an intravenousinjection of 0.5×10⁶ Raji cells/mouse. The mice were inoculatedintravenously to model disseminated disease. On Day 8 (7 days postinjection with the Raji cells), treatment Groups 3-5 received a single200 μl intravenous dose of TC1 cells per Table 15.

TABLE 15 Treatment groups Group Raji Cells (i.v.) TC1 Treatment (i.v.) N1 None None 8 2 0.5 × 10⁶ cells/mouse None 4 3 0.5 × 10⁶ cells/mouse 1 ×10⁶ cells/mouse 4 (~0.5 × 10⁶ CAR-T + cells) 4 0.5 × 10⁶ cells/mouse 2 ×10⁶ cells/mouse 4 (~1.0 × 10⁶ CAR-T + cells) 5 0.5 × 10⁶ cells/mouse 4 ×10⁶ cells/mouse 4 (~2.0 × 10⁶ CAR-T + cells)

During the course of the study mice were monitored daily and body weightwas measured two times weekly. A significant endpoint was the time toperi-morbidity and the effect of T-cell engraftment was also assessed.The percentage of animal mortality and time to death were recorded forevery group in the study. Mice were euthanized prior to reaching amoribund state. Mice may be defined as moribund and sacrificed if one ormore of the following criteria were met:

Loss of body weight of 20% or greater sustained for a period of greaterthan 1 week;

Tumors that inhibit normal physiological function such as eating,drinking, mobility and ability to urinate and or defecate;

Prolonged, excessive diarrhea leading to excessive weight loss (>20%);or

Persistent wheezing and respiratory distress.

Animals were also considered moribund if there was prolonged orexcessive pain or distress as defined by clinical observations such as:prostration, hunched posture, paralysis/paresis, distended abdomen,ulcerations, abscesses, seizures and/or hemorrhages.

Similar to the subcutaneous xenograph model (Example 12), theDisseminated Model revealed a statistically significant survivaladvantage in mice treated with TRAC⁻/B2M⁻ CD19CAR+ cells (TC1) as shownin FIG. 20, p<0.0001. The effect of TC1 treatment on survival in thedisseminated model was also dose dependent (Table 16).

TABLE 16 Animal survival Raji Cells TC1 Treatment Max survival Mediansurvival Group (i.v.) (i.v.) (days) (days) 1 No No Max Max 2 Yes No 2020 3 Yes 1 × 10⁶ cells/mouse 21 21 4 Yes 2 × 10⁶ cells/mouse 25 25 5 Yes4 × 10⁶ cells/mouse 32 26

A second experiment was run using the Intravenous Disseminated modeldescribed above.

On Day 1 mice in Groups 2-4 received an intravenous injection of 0.5×10⁶Raji cells/mouse. The mice were inoculated intravenously to modeldisseminated disease. On Day 4 (3 days post injection with the Rajicells), treatment Groups 2-4 received a single 200 μl intravenous doseof TC1 cells per Table 17.

TABLE 17 Treatment groups Group Raji Cells (i.v.) TC1 Treatment (i.v.) N1 0.5 × 10⁶ cells/mouse None 6 2 0.5 × 10⁶ cells/mouse 0.6 × 10⁶ CAR⁺cells/mouse 7 3 0.5 × 10⁶ cells/mouse 1.2 × 10⁶ CAR⁺ cells/mouse 5 4 0.5× 10⁶ cells/mouse 2.4 × 10⁶ CAR⁺ cells/mouse 5

Again, the Disseminated Model revealed a statistically significantsurvival advantage in mice treated with TRAC⁻/B2M⁻CD19CAR+ cells (TC1)as shown in FIG. 42A, p=0.0016. The effect of TC1 treatment on survivalin the disseminated model was also dose dependent (Table 18).

TABLE 18 Animal survival Raji TC1 Max Median Cells Treatment survivalsurvival Group (i.v.) (i.v.) (days) (days) Significance 1 Yes No 20 20 2Yes 0.6 × 10⁶ CAR⁺ 35 27 p = 0.005 cells/mouse 3 Yes 1.2 × 10⁶ CAR⁺ 3937 p = 0.016 cells/mouse 4 Yes 2.4 × 10⁶ CAR⁺ 49 46 p = 0.016cells/mouse

Evaluation of Splenic Response to TC1 Treatment

The spleen was collected from mice 2-3 weeks following Raji injectionand the tissue was evaluated by flow cytometry for the persistence ofTC1 cells and eradication of Raji cells in the spleen.

Flow Cytometry Analysis Procedure

The Spleen was transferred to 3 mL of 1×DPBS CMF in a C tube anddissociated using the MACS Octo Dissociator. The sample was transferredthrough a 100 micron screen into a 15 mL conical tube, centrifuged (1700rpm, 5 minutes, ART with brake) and resuspended in 1 mL of 1×DPBS CMFfor counting using the Guava PCA. Bone marrow was centrifuged andresuspended in 1 mL of 1×DPBS CMF for counting using the Guava PCA.Cells were resuspended at a concentration of 10×10⁶ cells/mL in 1×DPBSCMF for flow cytometry staining.

Specimens (50 μL) were added to 1 mL 1× Pharm Lyse and incubated for10-12 minutes at room temperature (RT). Samples were centrifuged andthen washed once with 1×DPBS CMF. Samples were resuspended in 50 μL of1×DPBS and incubated with Human and Mouse TruStain for 10-15 minutes atRT. The samples were washed once with 1 mL 1×DPBS CMF and resuspend in50 μL of 1×DPBS CMF for staining. Surface antibodies were added and thecells incubated for 15-20 minutes in the dark at RT and then washed with1 mL 1×DPBS CMF. Then samples were resuspended in 125 μL of 1×DPBS CMFfor acquisition on the flow cytometer.

Cells were stained with the following surface antibody panel:

TABLE 19 FITC PE APC C3 APCCy7 V421 V510 huCD3 huCD45 huCD19 7AAD CD8CD4 mCD45 (UCHT1) (HI30) (HIB19) (SK1) (RPA- (30-F11) T4)

Cell populations were determined by electronic gating (P1=totalleukocytes) on the basis of forward versus side scatter. Compensation toaddress spill over from one channel to another was performed uponinitial instrument set up using Ultra Comp Beads from Thermo Fisher. Theflow cytometer was set to collect 10,000 CD45+ events in each tube. Flowcytometric data acquisition was performed using the FACSCantoll™ flowcytometer. Data was acquired using BO FACSDiva™ software (version 6.1.3or 8.0.1). Flow cytometry data analysis was in the form of FlowCytograms, which are graphical representations generated to measurerelative percentages for each cell type.

This example demonstrates that following TC1 cell treatment, thetherapeutically beneficial TRAC⁻/B2M⁻CD19CAR+ cells persist in thespleen and selectively eradicate Raji cells from the tissue (FIG. 21A).In addition, treatment with TC1 cells do not exhibit Raji inducedincrease in cell mass (FIG. 21B). Further, FIG. 22 shows that theremaining human cells in spleens of mice treated with TRAC⁻/B2M⁻CD19CAR+cells are CD8+. These CD8+ T cells are also CD3 negative proving thatpersistent T cells in this model remain TCR/CD3 negative and are thusedited.

Intravenous Disseminated Nalm-6 Human Acute Lymphoblastic Leukemia TumorXenograft Model

The Intravenous Disseminated Model (Disseminated Model) using the Nalm-6Human Acute Lymphoblastic Leukemia tumor cell line in NOG mice was usedin this example to further demonstrate the efficacy ofTRAC⁻/B2M⁻CD19CAR+ cells. Generation of the TRAC⁻/B2M⁻CD19CAR+ cells(TC1) used in this model was described in the Examples above andevaluated in the Disseminated Model using methods employed byTranslations Drug Development, LLC (Scottsdale, Ariz.) and describedherein. In brief, 24, 5-8 week old female CIEA NOG(NOD.Cg-Prkdc^(scid)I12rg^(tm1Sug)/JicTac) mice were individually housedin ventilated microisolator cages, maintained under pathogen-freeconditions, 5-7 days prior to the start of the study. At the start ofthe study, the mice were divided into 5 treatment groups as shown inTable 20. On Day 1 mice in Groups 2-4 received an intravenous injectionof 0.5×10⁶ Nalm6 cells/mouse. The mice were inoculated intravenously tomodel disseminated disease. On Day 4 (3 days post injection with theNalm6 cells), treatment Groups 2-4 received a single 200 μl intravenousdose of TC1 cells per Table 20.

TABLE 20 Treatment groups Group Nalm6 Cells (i.v.) TC1 Treatment (i.v.)N 1 0.5 × 10⁶ cells/mouse None 6 2 0.5 × 10⁶ cells/mouse 1 × 10⁶ CAR⁺cells/mouse 6 3 0.5 × 10⁶ cells/mouse 2 × 10⁶ CAR⁺ cells/mouse 6 4 0.5 ×10⁶ cells/mouse 4 × 10⁶ CAR⁺ cells/mouse 6

During the course of the study mice were monitored daily and body weightwas measured two times weekly as described above.

Similar to the Raji intravenous disseminated model (above), the Nalm6Model also showed a statistically significant survival advantage in micetreated with TRAC⁻/B2M⁻ CD19CAR+ cells (TC1) as shown in FIG. 42B,p=0.0004. The effect of TC1 treatment on survival in the Nalm6disseminated model was also dose dependent (Table 21).

TABLE 21 Animal survival TC1 Max Median Nalm6 Treatment survivalSurvival Group Cells (i.v.) (i.v.) (days) (days) Significance 2 Yes No31 25.5 3 Yes 1 × 10⁶ CAR⁺ 32 31 p = 0.03 cells/mouse 4 Yes 2 × 10⁶ CAR⁺38 36 p = 0.0004 cells/mouse 5 Yes 4 × 10⁶ CAR⁺ 52 46 p = 0.0004cells/mouse

Example 14—TC1 Proliferation is Cytokine Dependent

The production of the TRAC⁻/B2M⁻CD19CAR+ cells, TC1, may result inunwanted off-target editing that could generate cells with adverseproperties. One of these adverse properties could be uncontrolled cellgrowth. In this experiment, we assessed the ability of TC1 cells to growin the absence of cytokines and/or serum.

1×10⁶ TC1 cells were plated ˜2 weeks post production (Day 0). The numberof viable cells were enumerated 7 and 14 days post plating in eitherfull media, 5% human serum without cytokines (IL-2 and IL-7), or basemedia lacking serum and cytokines. No cells were detected at 14 daysplated in the cultures that lacked cytokines suggesting that anypotential off-target effects due to genome editing did not bestow growthfactor independent growth/proliferation to TC1 cells. The TC1 cells onlyproliferated in the presence of cytokines (e.g. full media that containscytokines) and did not proliferate in the presence of serum alone asshown in FIG. 23. Thus, in vivo, the TC1 cells would likely not grow inthe absence of cytokine, growth factor or antigen stimulation due to anyoff-target genome editing.

Example 15—CRISPR/Cas9 Mediated Knockout of TCR and MHC I Components andExpression of CD70 Chimeric Antigen Receptor Constructs

This example describes the production by CRISPR/Cas9 and AAV6 ofallogeneic human T cells that lack expression of TCR, or TCR and MHC I,and express a chimeric antigen receptor targeting CD70+ cancers.

A schematic depiction of CRISPR/Cas9 generated allogeneic CAR−T cells isshown in FIG. 24A.

Similar to Example 9 above, CRISPR/Cas9 was used to disrupt (knockout[KO]) the coding sequence of the TCRa constant region gene (TRAC). Thisdisruption leads to loss of function of TCR and renders the gene editedT cell non-alloreactive and suitable for allogeneic transplantation,minimizing the risk of graft versus host disease (GVHD). The DNA doublestranded break at the TRAC locus was repaired by homology directedrepair with an AAV6-delivered DNA template containing right and lefthomology arms to the TRAC locus flanking a chimeric antigen receptorcassette (−/+ regulatory elements for gene expression). To reduce hostversus graft (HVG) (e.g.: host vs CAR−T) and allow for persistence ofthe allogeneic CAR−T product, the B2M gene was also disrupted usingCRISPR/Cas9 components. Together, these genome edits result in a T cellwith surface expression of a CAR (expressed from the TRAC locus)targeting CD70+ cancers along with loss of the TCR and MHC I, to reduceGVHD and HVG, respectively. The T cell can be referred to as aTRAC⁻/B2M⁻CD70CAR+ cell.

For certain experiments, described in the following examples, singleknock-out TRAC−CD70 CAR+ cells were also produced and tested.

A schematic of DNA plasmid constructs for production of recombinant AAVvirus carrying donor templates to facilitate targeted genomic insertionof CAR expression cassettes by HDR of Cas9-evoked site specific DNAdouble stranded breaks is shown in FIG. 24B.

TABLE 22 Donor Template Component Sequences SEQ ID NO: Domain NameLength (bp) 1313 Left ITR (5′ ITR) 145 1314 Right ITR (3′ ITR) 145 1423CD70A CAR 1518 1424 CD70B CAR 1518 1319 pA 49 1325 TRAC-LHA (800 bp) 8001326 TRAC-RHA (800 bp) 804 1331 EF1a 1178

CTX-142 and CTX-145 are derived from CTX-138 but the CAR has beenmodified to comprise anti-human CD70 scFV coding regions (FIG. 24B)instead of anti-CD19 scFV coding regions; in addition, the CAR ismodified to comprise an alternate signal peptide (e.g.: CD8;MALPVTALLLPLALLLHAARP (SEQ ID NO: 1586)) as compared to the CAR encodedby CTX-138. CTX-142 and CTX-145 are derived from CTX-138 but with theanti-CD19 scFv coding regions replaced with anti-human CD70 scFv codingregions (FIG. 24B). CTX-142 and CTX-145 differ in the orientation of theantiCD70 scFv variable heavy (VH) and variable light (VL) chains.CTX-142 (SEQ ID NO: 1358) contains an anti-CD70 CAR construct(antiCD70A: CD8[signal peptide]-VL-linker-VH-CD8[tm]-CD28[co-stimulatorydomain]-CD3z) (SEQ ID NO: 1423) with a synthetic 3′ poly adenylationsequence (pA) whose expression is driven by the EF1a promoter. The scFvis constructed such that the VL chain is amino terminal to the VH chain.CTX-142 (SEQ ID NO: 1358) also contains 800 bp homology arms flanking agenomic Cas9/sgRNA target site in the TRAC locus. CTX-145 (SEQ ID NO:1359) is similar to CTX-142, however the antiCD70 CAR construct(contains an antiCD70 CAR construct (antiCD70B: CD8[signalpeptide]-VH-linker-VL-CD8[tm]-CD28[co-stimulatory domain]-CD3z) (SEQ IDNO: 1424) switched the orientation of the VH and VL chains, the VH isamino terminal to the VL.

Anti CD70 CAR T cells were produced with CRISPR/Cas9 and AAV componentsas described (herein). Transgene insertion in primary human T cells viahomology directed repair (HDR) and concurrent gene knockout byCas9:sgRNA RNA was performed as described above in Examples 8 and 9.Primary human T cells were first electroporated with Cas9 or Cas9:sgRNARNP complexes targeting TRAC (AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 76);comprising sgRNA (SEQ ID NO: 1343) and B2M1 (GCTACTCTCTCTTTCTGGCC (SEQID NO: 417); comprising sgRNA (SEQ ID NO: 1345). The gRNAs used in thisExample comprise the following spacer sequences: TRAC gRNA spacer(AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152)); and B2M gRNA spacer(GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)).

sgRNA sequences can be modified as follows: TRAC SEQ ID NO: 1342, B2MSEQ ID NO: 1345.

The DNA double stranded break at the TRAC locus was repaired by homologydirected repair with an AAV6-delivered DNA template (CTX-142 orCTX-145).

Example 16—HDR-Mediated Concurrent Transgene Insertion in Cells toGenerate TRAC−CD70CAR+ and TRAC−B2M−CD70CAR+ Cells

This example demonstrates efficient transgene insertion and concurrentgene knockout by Cas9:sgRNA RNP (for double stranded break induction)and AAV6 delivered donor template (CTX-142 or CTX-145) containing a CD70CAR construct in primary human T cells.

Primary human T cells were activated with CD3/CD28 magnetic beads (asdescribed previously in Example 2). Three days later activation beadswere removed. The next day cells were electroporated with RNP complexesincluding sgRNAs targeting either TRAC alone, or TRAC+ B2M (2 separatelycomplexed RNPs). 7 days post manipulation, cells were analyzed by flowcytometry, as previously described herein and in Example 2.

Guides used in this example target:

TRAC: (SEQ ID NO: 76) AGAGCAACAGTGCTGTGGCC; and comprise TRAC sgRNA (SEQID NO: 1343) B2M: (SEQ ID NO: 417)GCTACTCTCTCTTTCTGGCC; and comprise B2M sgRNA (SEQ ID NO: 1345)

The gRNAs used in this Example comprise the following spacer sequences:TRAC gRNA spacer (AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152)); and B2M gRNAspacer (GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)).

sgRNA sequences can be modified as follows: TRAC SEQ ID NO: 1342, B2MSEQ ID NO: 1344.

FIG. 25A shows that cells treated with TRAC sgRNA containing RNP andCTX-145 AAV6 produced higher levels of expression of a CAR construct,while cells treated with a TRAC sgRNA RNP and CTX-142 AAV6 were not aseffective at producing CD70 CAR expressing cells. FIG. 25B demonstratesnormal proportions of CD4/CD8 T cell subsets maintained in the TRACnegative CAR+ fraction from cells treated with TRAC sgRNA containing RNPand CTX-145 AAV6, suggesting that the expression of a geneticallyengineered anti CD70 CAR T cell affects the proportion of T cellsubsets.

In addition, cells infected with AAV6 encoding CTX-145 alone do notexpress high levels of anti CD70 CAR. A double stranded break induced bya TRAC sgRNA containing RNP and subsequent repair by HDR using CTX-145donor template is required for surface expression of anti CD70 CAR (FIG.26). Thus, the CTX-145 construct is only expressed following integrationinto the TRAC gene and would not be expressed in cells that were nottreated with both the TRAC RNP and AAV vector.

FIG. 27 demonstrates successful production of single human T cellslacking TCR and B2M surface expression with concurrent expression of theCD70 CAR from an integrated transgene in the TRAC locus using themethods described above (TCR−/B2M− CD70CAR+).

The percentage of cells expressing CD70 was tracked during theproduction of CD70 CAR−T cells. At day 0 a small percentage of T cellsexpress CD70 and are mostly CD4+(FIG. 36A). These percentages areconsistent 4 days post electroporation/infection with AAV6 except incells that become CD70CAR+. CD70CAR+ cultures lack cells expressingCD70. The high frequency of CD70CAR+ cells along with the lack of CD70expression in antiCD70-CAR+ cultures suggests that CD70+ T cells serveas targets of antiCD70-CART cells which leads to the fratricide of CD70+T cells along with the expansion of antiCD70− CAR−T cells (FIG. 36B—Toppanel corresponds to CD70− cells from FIG. 36A; Bottom panel correspondsto CD70+ cells from FIG. 36A).

Example 17—Generation of CD70 Expressing Cell Lines

K562 cells were infected with lentiviral particles encoding a human CD70cDNA under the control of the EF1a promoter as a well as a puromycinexpression cassette (Genecopoeia). Cells were selected in 2 mg/mLpuromycin for 4-7 days and assayed for CD70 surface expression using anAlexa fluor 647 conjugated anti-CD70 antibody (Biolegend, 355115). FIG.28A demonstrates high surface expression of CD70 on CD70 overexpressingK562 cells (CD70+K562) compared to parental K562 cells and comparableexpression levels to native CD70 expressed on the Raji cell line.

A panel of other cell lines was also tested for CD70 surface expressionusing flow cytometry: Nalm6 (lymphoid), 293 (embryonic kidney), ACHN(renal), Caki-2 (renal), Raji (lymphoid), Caki-1 (renal), A498 (renal),and 786-O (renal). The results are shown in FIG. 28B. Raji, Caki-1 andA498 cell lines exhibited the highest levels of CD70 surface expressionin this assay. These cell lines and the CD70 expressing K562 cells canbe used to evaluate effector function and specificity of TCR−/anti-CD70CAR+ and TCR−/B2M−/anti-CD70 CAR+.

Example 18—Evaluation of Effector Function in CRISPR/Cas9 Modified TCells Expressing a CD70 Chimeric Antigen Receptor (CAR)

Interferon Gamma Stimulation by Genetically Engineered T CellsExpressing a CD70 CAR

The ability of the engineered cells to produce interferon gamma (IFNγ)in a target cell was analyzed using an ELISA assay, as described aboveand in Example 10.

The specificity of genetically modified T cells expressing a CD70 CARintegrated into the TRAC gene, was evaluated in an in vitro ELISA assay.IFNγ from supernatants of cell co-cultures was measured. OnlyTRAC⁻/anti-CD70 CAR+ cells secrete high levels of IFNγ when culturedwith CD70+K562. IFNγ secretion was not detected when TRAC⁻/anti-CD70CAR+ cells were cultured with K562 cells that were not engineered tooverexpress surface CD70 (FIG. 5A) (at a 4:1 CAR−T cell to targetratio).

Similarly, the TRAC⁻/anti-CD70CAR+ cells only stimulated IFNγ CD70+ Rajicells, but not the CD70− Nalm6 cells (FIG. 29B) (at a 2:1 CAR−T cell totarget ratio). TRAC⁻/anti-CD70 CAR+ T cells did not secrete detectablelevels of IFNγ when cultured by themselves in the absence of targetcells (FIG. 29C).

GranzymeB Assay

To further assess the effector functions of TRAC−/anti-CD70CAR+ cells,intracellular GranzymeB levels in target cells were measured in asurrogate cell lysis assay. Target cells that are GranzymeB+ hadperforin containing membrane pores formed and subsequent injection ofGranzymeB through the pores to initiate apoptosis by theTRAC−/anti-CD70CAR+ cells. The GranToxiLux assay was performed witheither Raji cells (CD70 positive cells) or Nalm6 cells (CD70 negativecells) according to the manufacturer's instructions (Oncoimmunin Inc.).Fluorescently labeled target cells were co-cultured at a 2:1 ratio withtest T cells (e.g.: TRAC⁻/anti-CD70CAR+:Target cells) in GranzymbeBsubstrate for 2 hrs at 37° C. Cells were then washed and % of targetcells positive for GranzymbeB activity was quantitated by flowcytometry. Other control test cells were also evaluated at similarratios (unedited T cells (TRC+) and TRAC⁻ T cells). FIG. 29B showsefficient GranzymeB insertion and activity by TRAC⁻/anti-CD70CAR+ cellsonly in Raji cells (CD70+) and not in Nalm6 cells (CD70⁻). The othercontrol cells tested did not induce GranzymeB insertion and activity inany target cell type. Thus, TRAC⁻/anti-CD70CAR+ cells can induce lysisof CD70 positive target cells.

Cell Kill Assay in Adherent Renal Cell Carcinoma—in the Context of CD28Co-Stim

To assess the ability of CRISPR/Cas9 modified T cells expressing a CD70CAR to kill CD70 expressing adherent renal cell carcinoma (RRC) derivedcell lines, a cell killing assay was devised. Adherent cells were seededin 96-well plates at 50,000 cells per well and left overnight at 37° C.The next day T cells were added to the wells containing target cells ata 2:1 ratio. After the indicated incubation period, T cells were removedfrom the culture by aspiration and 100 μL Cell titer-Glo (Promega) wasadded to each well of the plate to assess the number of remaining viablecells. The amount of light emitted per well was then quantified using aplate reader. TRAC⁻CD70CAR+ cells induced potent cell killing of renalcell carcinoma derived cell lines after a 72 hr co-incubation (FIG.30A), while control test cells (control T cells: TCR+ or TRAC−) had noeffect. As expected, the TRAC⁻CD70CAR+ cells did not exhibit any abilityto lyse a CD70 negative human embryonic kidney derived cell line (HEK293or 293). Staurosporine (Tocris) was used as a positive control to showthat the levels of cell killing induced by a small molecule wascomparable between the 3 target cell types tested. These resultsdemonstrate that cell lysis induced by TRAC⁻CD70CAR+ cell is specifictoward target cells expressing surface CD70. In addition, CRISPR/Cas9modified T cells expressing a CD70 CAR exhibited potent cell lysis of aseries of CD70 expressing renal cell carcinoma derived cell lines (FIGS.30B and 30C).

Evaluation of Costimulatory Domains 41Bb and CD28 in Anti-CD70 CAR TCells

CTX145b (SEQ ID NO: 1360) is derived from CTX145 whereCD28[co-stimulatory domain] has been replaced by 41BB [co-stimulatorydomain] (FIG. 61). The 4-1BB domain sequence is

(nucleotide-SEQ ID NO: 1339)AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG; (amino acid-SEQ ID NO: 1340)KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL.

Efficient Creation of TRAC, B2M Double Knockout Anti-41BB-CD70 CAR−TCells

This example demonstrates efficient transgene insertion and concurrentgene knockout by Cas9:sgRNA RNP (for double-stranded break induction)and AAV6 delivered donor template (CTX-145b (SEQ ID NO: 1360))containing a CD70 CAR construct in primary human T cells. The productionof allogenic human T cells is as described in Example 16. The highefficiency is similar when using AAV6 delivered donor template CTX-145(SEQ ID NO: 1359) and CTX145b (89.7% CAR+ cells using CTX-145 v. 88.6%CAR+ cells using CTX-145b, compared to 2.38% CAR+ cells with control (nodonor template)).

FIG. 62 demonstrates normal proportions of CD4/CD8 T cell subsetsmaintained in the TRAC−/B2M−/anti-CD70(4-1BB co-stim) CAR+ fraction fromcells treated with TRAC and B2M sgRNA containing RNPs and CTX-145b AAV6,suggesting that the expression of a genetically engineered T cellsexpressing an anti-CD70 CAR that has a 4-1BB co-stimulatory domain doesnot affect significantly the proportion of T cell subsets.

Efficient Production of PD1, TRAC, B2M Triple Knockout Anti-CD70 CAR−TCells, with a 4-1BB or a CD28 Costimulatory Domain

This example demonstrates efficient transgene insertion and concurrentgene knockout by Cas9:sgRNA RNP (for double stranded break induction)and AAV6 delivered donor template (CTX-145 or CTX-145b) containing ananti-CD70 CAR construct in primary human T cells. The production ofallogenic human T cells is as described in Example 24, where CTX-138 wasreplaced by CTX-145 (CD28 co-stim) or CTX-145b (4-1BB co-stim).

The high efficiency was similar when using AAV6-delivered donor template(compare CTX-145 and CTX145b) (FIG. 63). 80% of the engineered T cellsexpressed the anti-CD70 CAR having the CD28 co-stim domain, wherein 82%expressed the anti-CD70 CAR having the 4-1BB co-stim domain.

FIG. 64 shows that normal proportions of CD4/CD8 T cell subsets weremaintained in the PD1−/TRAC−/B2M−/anti-CD70 CAR+ fraction from cellstreated with PD1, TRAC and B2M sgRNA containing RNPs and CTX-145b AAV6,suggesting that expression of an anti-CD70 CAR that has a 4-1BBco-stimulatory domain in genetically engineered T cells does not affectsignificantly the proportion of T cell subsets.

Cell Kill Assay in Adherent Renal Cell Carcinoma

To assess the ability of CRISPR/Cas9 modified T cells expressing ananti-CD70 CAR to kill CD70 expressing adherent renal cell carcinoma(RRC) derived cell lines, a cell killing assay was devised as describedabove. TRAC−/B2M−/anti-CD70 CAR+ cells demonstrated potent cell killingof renal cell carcinoma derived cell lines (A498 cells) after 24 hoursco-incubation (FIG. 65), in the context of both costimulatory domainsCD28 and 41BB, compared to control test cells (control T cells: TCR+).PD1−/TRAC−/B2M−/anti-CD70 CAR+ cells induced similar potent cell killingof A498 cells with the 4-1BB costimulatory domain (compared to double KOcells), but lower potency with CD28 costimulatory domain (FIG. 65).

FIG. 66 shows that TRAC−/B2M−/anti-CD70 (4-1BB or CD28) CAR+ cells andPD1−/TRAC−/B2M−/anti-CD70 (4-1BB or CD28) CAR+ cells induced potent cellkilling of CD70 expressing adherent renal cell carcinoma (RRC) derivedcell line, ACHN at a 3:1 ratio T cell:target cell.

Example 19—Anti-BCMA CAR T Cells

CRISPR/Cas9 Mediated Knockout of TCR and MHC I Components and Expressionof BCMA Chimeric Antigen Receptor Constructs

This example describes the production by CRISPR/Cas9 and AAV6 ofallogeneic human T cells that lack expression of TCR, or TCR and MHC I,and express a chimeric antigen receptor targeting BCMA+ cancers.

A schematic depiction of CRISPR/Cas9 generated allogeneic CAR−T cells isshown in FIG. 31A.

Similar to Example 9 and 15 above, CRISPR/Cas9 was used to disrupt(knockout [KO]) the coding sequence of the TCRa constant region gene(TRAC). This disruption leads to loss of function of TCR and renders thegene edited T cell non-alloreactive and suitable for allogeneictransplantation, minimizing the risk of graft versus host disease(GVHD). The DNA double stranded break at the TRAC locus was repaired byhomology directed repair with an AAV6-delivered DNA template containingright and left homology arms to the TRAC locus flanking a chimericantigen receptor cassette (−/+ regulatory elements for gene expression).To reduce host versus graft (HVG) (e.g.: host vs CAR−T) and allow forpersistence of the allogeneic CAR−T product, the B2M gene was alsodisrupted using CRISPR/Cas9 components. Together, these genome editsresult in a T cell with surface expression of a CAR (expressed from theTRAC locus) targeting BCMA+ cancers along with loss of the TCR and MHCI, to reduce GVHD and HVG, respectively. The T cell can be referred toas a TRAC⁻/B2M⁻/anti-BCMA CAR+ cell.

For certain experiments, described in the following examples, singleknock-out TRAC−BCMA CAR+ cells were also produced and tested.

A schematic of DNA plasmid constructs for production of recombinant AAVvirus carrying donor templates to facilitate targeted genomic insertionof CAR expression cassettes by HDR of Cas9-evoked site specific DNAdouble stranded breaks is shown in FIG. 31B.

TABLE 23 Donor Template Component Sequences SEQ ID NO: Domain NameLength (bp) 1313 Left ITR (5′ ITR) 145 1314 Right ITR (3′ ITR) 145 1425BCMA-1 CAR 1512 1426 BCMA-2 CAR 1512 1317 2A 66 1318 EGFP 720 1319 pA 491325 TRAC-LHA (800 bp) 800 1326 TRAC-RHA (800 bp) 804 1331 EF1a 1178

CTX-153 (SEQ ID NO: 1362) and CTX-155 (SEQ ID NO: 1364) are derived fromCTX-145 but with the anti-CD70 scFv coding region of CTX-145 is replacedwith anti-human BCMA scFv coding region (FIG. 31B and FIG. 14). CTX-152(SEQ ID NO: 1361) and CTX-154 (SEQ ID NO: 1363) differs from CTX-153 andCTX-155, respectively, by the addition of the picornavirus 2A and GFPsequences. CTX-152, CTX-153, CTX-154, and CTX-155, all contain homologyarms flanking a genomic Cas9/sgRNA target site in the TRAC locus.CTX-152 and CTX-153 contain 800 bp homology arms, while CTX-154 (SEQ IDNO: 1363) and CTX-155 contain 500 bp homology arms (FIG. 31B). CTX-152(SEQ ID NO: 1361) and CTX-154 differ from each other in the orientationof the anti-BCMA scFv variable heavy (VH) and variable light (VL)chains. CTX-152 (SEQ ID NO: 1361) contains an anti-BCMA CAR construct(anti-BCMA (nucleotide sequence (SEQ ID NO: 1425); amino acid sequence(SEQ ID NO: 1451)): CD8[signalpeptide]-VH-linker-VL-CD8[tm]-CD28[co-stimulatory domain]-CD3z) with asynthetic 3′ poly adenylation sequence (pA) whose expression is drivenby the EF1a promoter. The scFv is constructed such that the VH chain isamino terminal to the VL chain. CTX-154 is similar to CTX-152, howeverthe anti-BCMA CAR construct (contains an anti-BCMA CAR construct(anti-BCMA (nucleotide sequence (SEQ ID NO: 1426); amino acid sequence(SEQ ID NO: 1452): CD8[signalpeptide]-VL-linker-VH-CD8[tm]-CD28[co-stimulatory domain]-CD3z) switchedthe orientation of the VH and VL chains, the VL is amino terminal to theVH.

The VH and VL chains that were used to construct the anti-BCMA scFvs areBCMA_VH1 (SEQ ID NO: 1523) and BCMA_VL1 (SEQ ID NO: 1525), respectively.These chains were derived from mouse antibodies. A humanized version ofthe VH sequence have been constructed (SEQ ID NO: 1524) and twohumanized versions of the VL sequence have been constructed (SEQ ID NOs:1526 and 1527). These were used to construct humanized anti-BCMAconstructs scFv BCMA-3, scFv BCMA-4, scFv BCMA-5 and scFv BCMA-6 (SEQ IDNOs: 1503-1506) using the method described above. Any one of these scFvscan be used to construct CAR constructs as described previously. Thehumanized scFv CAR constructs have the linker sequence ofGGGGSGGGGSGGGGS (SEQ ID NO: 1341).

Additional anti-BCMA scFvs were constructed using the method describedabove. For example, VH and VL chains BCMA_VH2 (SEQ ID NO: 1528) andBCMA_VL2 (SEQ ID NO: 1529) can be used to construct anti-BCMA scFvs.These variable chains were used to construct the anti-BCMA constructsscFv BCMA-7 (VH-VL; SEQ ID NO: 1507) and scFv BCMA-8 (VL-VH; SEQ ID NO:1508). Any one of these scFvs can be used to construct CAR constructs asdescribed previously.

In another example, the VH and VL chains BCMA_VH3 (SEQ ID NO: 1530) andBCMA_VL3 (SEQ ID NO: 1531) were used to construct anti-BCMA scFvs.Specifically, these variable chains were used to construct the anti-BCMAconstructs scFv BCMA-9 (VH-VL; SEQ ID NO: 1513) and scFv BCMA-10 (VL-VH;SEQ ID NO: 1514). Any one of these scFvs can be used to construct CARconstructs as described previously. Anti BCMA CAR T cells were producedwith CRISPR/Cas9 and AAV components as described (herein). Transgeneinsertion in primary human T cells via homology directed repair (HDR)and concurrent gene knockout by Cas9:sgRNA RNA was performed asdescribed above in Examples 8 and 9. Primary human T cells were firstelectroporated with Cas9 or Cas9:sgRNA RNP complexes targeting TRAC(AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 76); sgRNA (SEQ ID NO: 1343) and B2M1(GCTACTCTCTCTTTCTGGCC (SEQ ID NO: 417); sgRNA (SEQ ID NO: 1345).

sgRNA sequences can be modified as follows: TRAC SEQ ID NO: 1342, B2MSEQ ID NO: 1344.

The DNA double stranded break at the TRAC locus was repaired by homologydirected repair with an AAV6-delivered DNA template (CTX-152, orCTX-154).

High Efficiency Multi-Editing by CRISPR/Cas9 to Produce Anti-BCMA CAR−TCells

Multi-editing resulted in decreased surface expression of TCR and MHC-I,as well as high CAR expression. More than 60% T-cells possessed allthree (TCR−/β2M−/anti-BCMA CAR+) or four (TCR−/β2M−/PD1−/anti-BCMA CAR+)desired modifications (FIG. 58A). Similar editing efficiencies wereobserved with double or triple knockouts. The CD4/CD8 ratios remainedsimilar in multi-edited anti-BCMA CAR−T cells (FIG. 58B). Multi-editedanti-BCMA CAR−T cells remained dependent on cytokines for growthfollowing multi-CRISPR/Cas9 editing (FIG. 58C).

The following gRNA spacer sequences were used in this example:

(SEQ ID NO: 152) TRAC: AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 466)B2M: GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 1086) PD1: CUGCAGCUUCUCCAACACAU

The donor template used in this example was SEQ ID NO: 1408 (LHA to RHAof CTX-166), which includes the anti-BCMA CAR comprising SEQ ID NO:1434.

Multi-Edited Anti-BCMA CAR−T Cells Show Improved Anti-Cancer Properties

Anti-BCMA CAR−T cells efficiently and selectively killed theBCMA-expressing MM cell line MM.1S in a 4-hour cell kill assay, whilesparing the BCMA-negative leukemic line K562 (FIG. 59A). Differences inresponse were notable at the lower T cell concentrations between doubleand triple knockout multi-edits. The cells also selectively secreted theT cell activation cytokines, IFNγ and IL-2, which are upregulated inresponse to induction only by BCMA+ MM.1S cells (FIG. 59B).

PD1 KO Reduces Expression of Lag3 Exhaustion Marker in Long-Term InVitro Culture

No change in Lag3 exhaustion marker was observed between double(TCR−/β2M−/anti-BCMA CAR+) or triple (TCR−/β2M−/PD1−/anti-BCMA CAR+) KOanti-BCMA CAR−T cells after 1 week in culture. However, following four(4) weeks in culture, Lag3 expression was reduced in the triple KOanti-BCMA CAR−T cells indicating that the cells with the PD1 KO wereless exhausted.

TABLE 24 Example BCMA Constructs Construct Donor Template CAR CAR scFvscFv SEQ ID NO: (nucleic acid) SEQ ID NO: SEQ ID NO: SEQ ID NO: SEQ IDNO: Constructs* (nucleic acid) LHA to RHA (nucleic acid) (amino acid)(nucleic acid) (amino acid) CTX-152 1361 1397 1425 1451 1477 1501CTX-153 1362 1398 1425 1451 1477 1501 CTX-154 1363 1399 1426 1452 14781502 CTX-155 1364 1400 1426 1452 1478 1502 CTX-160 1365 1401 1427 14531479 1503 CTX-161 1367 1403 1429 1455 1480 1504 CTX-162 1368 1404 14301456 1481 1505 CTX-163 1369 1405 1431 1457 1482 1506 CTX-164 1370 14061432 1458 1483 1507 CTX-165 1371 1407 1433 1459 1484 1508 CTX-166 13721408 1434 1460 1485 1509 CTX-167 1374 1410 1436 1462 1486 1510 CTX-1681375 1411 1437 1463 1487 1511 CTX-169 1376 1412 1438 1464 1488 1512CTX-170 1377 1413 1439 1465 1489 1513 CTX-171 1378 1414 1440 1466 14901514 CTX-172 1379 1415 1441 1467 1491 1515 CTX-173 1380 1416 1442 14681492 1516 CTX-174 1381 1417 1443 1469 1493 1517 CTX-175 1382 1418 14441470 1494 1518 CTX-176 1383 1419 1445 1471 1495 1519 CTX-177 1384 14201446 1472 1496 1520 CTX-178 1385 1421 1447 1473 1497 1521 CTX-179 13861422 1448 1474 1498 1522

It should be understood that for any one of the constructs provided inTable 24, the scFv fragment of the CAR may be substituted with any otherscFv fragment listed in Table 24.

Example 20—HDR-Mediated Concurrent Transgene Insertion in Cells toGenerate TRAC−B2M−BCMA CAR+ Cells

This example demonstrates efficient transgene insertion and concurrentgene knockout by Cas9:sgRNA RNP (for double stranded break induction)and AAV6 delivered donor template (CTX-152 or CTX-154) containing a BCMACAR construct in primary human T cells.

Primary human T cells were activated with CD3/CD28 magnetic beads (asdescribed previously in Example 2). Three days later activation beadswere removed. The next day cells were electroporated with RNP complexesincluding sgRNAs targeting TRAC or B2M (2 separately complexed RNPs). 7days post manipulation, cells were analyzed by flow cytometry, aspreviously described herein and in Example 2.

Guides used in this example target:

TRAC: (SEQ ID NO: 76) AGAGCAACAGTGCTGTGGCC; and compriseTRAC sgRNA (SEQID NO: 686) B2M: (SEQ ID NO: 417)GCTACTCTCTCTTTCTGGCC; and comprise B2M sgRNA (SEQ ID NO: 688)

The gRNAs used in this Example comprise the following spacer sequences:TRAC gRNA spacer (AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152)); and B2M gRNAspacer (GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)).

sgRNA sequences can be modified as follows: TRAC SEQ ID NO: 1342, B2MSEQ ID NO: 1345.

FACS analysis demonstrated that 77% of T cells were TRAC−, B2M−following treatment with TRAC sgRNA contain RNP and B2M sgRNA containingRNP (FIG. 32—top panels). In addition, the gene edited cells expressedthe CAR construct as evidenced by positive GFP expression andrecombinant BCMA binding (FIG. 32—bottom panels).

FIG. 32 demonstrates successful production of single human T cellslacking TCR and B2M surface expression with concurrent expression of theBCMA CAR from an integrated transgene in the TRAC locus using themethods described above (TCR−/B2M− BCMA CAR+).

Example 21—Evaluation of Effector Function in CRISPR/Cas9 Modified TCells Expressing a BCMA Chimeric Antigen Receptor (CAR)

Cell Kill Assay in BCMA Expressing Cells

To assess the ability of TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells to killsuspension cell lines a flow cytometry based cell killing assay wasdesigned. The TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells (see Example 19 forTable of CARs used) were co-cultured with cells of the BCMA-expressingRPMI8226 (ATCC Cat #ATCC-155) human plasmacytoma target cell line, cellsof the BCMA-expressing U-266 cell line, or cells of the K562 cell line,which do not express BCMA (collectively referred to as the “targetcells”. The target cells were labeled with 5 μM efluor670(eBiosciences), washed and incubated in co-cultures with theTRAC⁻/B2M⁻/anti-BCMA CAR+ T cells at varying ratios (from 0.1:1 to 8:1 Tcells to target cells) at 50,000 target cells per well of a U-bottom96-well plate overnight. The next day wells were washed, media wasreplaced with 200 μL of media containing a 1:500 dilution of 5 mg/mLDAPI (Molecular Probes) (to enumerate dead/dying cells). Finally, 25 μLof CountBright beads (Life Technologies) was added to each well. Cellswere then processed by flow cytometry.

Target cells per μL were then calculated from analyzed flow cytometrydata:Cells/μL=((number of live target cell events)/(number of beadevents))×((Assigned bead count of lot (beads/50 μL))/(volume of sample))

Total target cells were calculated by multiplying cells/μL×the totalvolume of cells.

The percent cell lysis was then calculated with the following equation:% Cell lysis=(1−((Total Number of Target Cells in Test Sample)/(TotalNumber of Target Cells in Control Sample))×100

FIG. 33A, FIG. 45B, and FIG. 46B (left graph) show thatTRAC−/B2M−/anti-BCMA CAR+ T cells selectively killed RPMI 8226 cells atlow T cell to BCMA-expressing target cell ratios; FIG. 46A (left graph)shows that TRAC−/B2M−/anti-BCMA CAR+ T cells selectively killed U-266cells (ATCC® TIB-196™); and FIG. 46C (left graph) shows thatTRAC−/B2M−/anti-BCMA CAR+ T cells showed no specific toxicity towardK562 cells (which lack BCMA expression). The results indicate that theCRISPR/Cas9 modified T cells described herein, induce potent cell lysisin BCMA expressing plasmacytoma cell line.

Interferon Gamma Stimulation by Genetically Engineered T CellsExpressing a BCMA CAR

The ability of the engineered cells to produce interferon gamma (IFNγ)in a target cell was analyzed using an ELISA assay, as described aboveand in Example 10 and 18.

The specificity of genetically modified T cells expressing an anti-BCMACAR integrated into the TRAC gene, was evaluated in an in vitro ELISAassay. IFNγ from supernatants of cell co-cultures was measured. RPMI8226cells were cultured with genetically engineered T cells expressing theanti-BCMA CAR, or controls. FIG. 33B demonstrates thatTRAC⁻/B2M⁻/anti-BCMA CAR+ T cells (cells expressing CTX152 or CTX154)secrete higher levels of IFNγ when cultured with RPMI8226 (ATCC Cat#ATCC-155) cells as compared to T cells that do not express theanti-BCMA CAR (no RNP/AAV) (at a 0.2:1, 1:1, 2:1, and 4:1 CAR−T cell totarget ratio). Similarly, FIG. 46B (right graph) and FIG. 47Bdemonstrate that TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells secrete higher levelsof IFNγ when cultured with RPMI8226 (ATCC Cat #ATCC-155) cells ascompared to the controls. FIG. 46A (right graph) shows thatTRAC⁻/B2M⁻/anti-BCMA CAR+ T cells also secrete higher levels of IFNγwhen cultured with U-266 cells. By contrast, FIG. 46C (right graph) andFIG. 47A show that TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells do not secrete IFNγwhen cultured with K562 cells (cells that do not express BCMA). Thus,not only do the anti-BCMA CAR T cells of the present disclosure produceIFNγ, they do so specifically in the presence of BCMA-expressing cells.

Example 22—Assessment of HDR Frequencies in CD19 CAR−T Cells Produced byCRISPR-Cas9

A droplet digital PCR (ddPCR) assay was designed to measure theefficiency of integration of the CAR construct (CTX-138) into the TRAClocus. The primers and probes used in the ddPCR assay are shown in Table25. SEQ ID NO: 1554-1556 were used to detect integration of the CARconstruct, and SEQ ID NOs: 1557-1559 were used to amplify a controlreference genomic region.

Forty (40) ng of genomic DNA was used in ddPCR reactions, dropletsgenerated and then run in a thermocycler under the conditions shown inTable 26 and Table 27.

The percentage of cells that stained CD19 CAR+ by flow cytometry wasplotted against the percentage of cells that were positive for anintegrated CAR construct from 4 healthy donor TRAC−B2M− CAR−T cells(FIG. 34). The ddPCR results show a strong correlation between CD19 CARexpression and HDR frequency (R²=0.88), indicating that we achievedsite-specific integration and high expression levels of the CD19 CARconstruct into the TRAC locus of T cells using CRISPR gene editing.

TABLE 25 Primers and Probes used in ddPCR assay SEQ ID Primers/ProbesSequence Locus NO: EH_TRAC_dPCR_F5 AGAAGGATAAGATGGCGGAGG TRAC 1554EH_TRAC_dPCR_R5 GCTTTCTGGCGTCCTTAGAA TRAC 1555 EH_TRAC_Probe_3end_2TCTACCCTCTCATGGCCTAGAAGG TRAC 1556 EH_control_1kb_F1TGGAGTGATTAGGAACATGAGCT Control 1557 EH_control_1kb_R1AAGCTCAAGCACTTCTAGTTAGAAAC Control 1558 EH_control_1kb_probe_1ATTCCACCCCACCTTCACTAAG Control 1559

TABLE 26 PCR mixture 1× 2× Droplet PCR Supermix 12.5 Forward Primer (18uM) 1.25 Reverse Primer (18 uM) 1.25 Probe (5 uM) 1.25 Forward Primer(18 uM) 1.25 Reverse Primer (18 uM) 1.25 Probe (5 uM) 1.25 H20 Mixvolume 20

TABLE 27 PCR conditions Duration # Cycles Temp of Cycle 1 95 C. 10 min40 90 C. 30 sec 59 C. 1 min 72 C. 3 min 1 98 C. 10 min 1  4 C. forever

Example 23—Evaluation of Effector Function of TRAC−/B2M−/Anti-CD19 CAR+T Cells on a B-ALL Cell Line

In this example the effector functions of TRAC−/B2M−/anti-CD19 CAR+ Tcells when co-cultured with the Nalm6 human B-ALL cell line wereassessed.

GranzymeB Assay

To further assess the effector functions of TRAC−/B2M−/anti-CD19 CAR+ Tcells, intracellular GranzymeB levels in target cells were measured in asurrogate cell lysis assay. GranzymeB secretion was assessed asdescribed in Example 18. TRAC−/B2M−/anti-CD19 CAR+ T cells or controlcells were cocultured with the Nalm6 cell line. As shown in FIG. 35A,TRAC−/B2M−/anti-CD19 CAR+ T cells co-cultured with the Nalm6 human B-ALLcell line at a 4:1 ratio exhibit efficient GranzymeB insertionindicating that TRAC−/B2M−/anti-CD19 CAR+ T cells can induce lysis ofthe CD19 positive Nalm6 B-ALL cell line.

Interferon Gamma Stimulation by Genetically Engineered T CellsExpressing a CD19 CAR

The ability of the engineered cells to produce interferon gamma (IFNγ)in a target cell was analyzed using an ELISA assay, as herein and inExample 10.

IFNγ from supernatants of cell co-cultures was measured.TRAC⁻/B2M⁻/anti-CD19 CAR+ T cells secrete high levels of IFNγ whencultured with CD19 positive Nalm6 cells, as shown in FIG. 35B.

Cell Kill Assay for Suspension Cell Lines

To assess the ability of TRAC⁻/B2M⁻/anti-CD19 CAR+ T cells to killsuspension cell lines a flow cytometry based cell killing assay wasdesigned. Cells were co-cultured with the Nalm6 human B-cell acutelymphoblastic leukemia (B-ALL) target cell line. The Nalm6 target cellswere labeled with 5 μM efluor670 (eBiosciences), washed and incubated inco-cultures with T cells at varying ratios (from 0.1:1 to 8:1 T cells totarget cells) at 50,000 target cells per well of a U-bottom 96-wellplate overnight. The next day wells were washed, media was replaced with200 μL of media containing a 1:500 dilution of 5 mg/mL DAPI (MolecularProbes) (to enumerate dead/dying cells). Finally, 25 μL of CountBrightbeads (Life Technologies) was added to each well. Cells were thenprocessed by flow cytometry.

Cells per μL were then calculated from analyzed flow cytometry data:Cells/μL=((number of live target cell events)/(number of beadevents))×((Assigned bead count of lot (beads/50 μL))/(volume of sample))

Total cells were calculated by multiplying cells/μL× the total volume ofcells.

The percent cell lysis was then calculated with the following equation:% Cell lysis=(1−((Total Number of target Cells in Test Sample)/(TotalNumber of Target Cells in Control Sample))×100.

FIG. 35C shows that TRAC−/B2M−/anti-CD19 CAR+ T cells selectively killedNalm6 cells at low T to target cell ratios. The results indicate thatthe CRISPR/Cas9 modified T cells described herein, induce potent celllysis in CD19 expressing acute lymphoblastic leukemia cell line.

Example 24—Creation of PD1, B2M, TRAC Triple Knockout Anti-CD19 CAR−TCells

This example describes the production by CRISPR/Cas9 and AAV6 ofallogeneic human T cells that lack expression of the TCR, MHC I, and PD1and express a chimeric antigen receptor targeting CD19+ cancers.

CRISPR/Cas9 and AAV6 were used as above (see for example, Examples 8-10and 12) to create human T cells that lack expression of the TCR, B2M andPD1 with concomitant expression from the TRAC locus using a CARconstruct targeting CD19 (CTX-138; SEQ ID NO: 675). In this exampleactivated T cells were electroporated with 3 distinct RNP complexescontaining sgRNAs targeting TRAC (e.g.: SEQ ID NO: 76), B2M (e.g.: SEQID NO: 417 and PD1 (CTGCAGCTTCTCCAACACAT (SEQ ID NO: 916)). The gRNAsused in this Example comprise the following spacer sequences: TRAC gRNAspacer (AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152)); B2M gRNA spacer(GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)); and PD1 gRNA spacer(CUGCAGCUUCUCCAACACAU (SEQ ID NO: 1086)). About 1 week postelectroporation cells were either left untreated or treated withPMA/ionomycin overnight. The next day cells were processed for flowcytometry. FIG. 58A shows that only cells treated with PD1 sgRNAcontaining RNP do not upregulate PD1 surface levels in response to anovernight treatment of PMA/ionomycyin.

Example 25—Efficacy of CD70 CAR+ T Cells: The Subcutaneous Renal CellCarcinoma Tumor Xenograft Model in NOG Mice

NOG mice were injected subcutaneously with 5×10⁶ A498 renal cellcarcinoma cells. At day 10 post inoculation mice were either leftuntreated or injected intravenously (I.V.) with a therapeutic dose of1×10⁷ or 2×10⁷ anti-CD70 CAR−T cells. Tumor volumes were measured every2 days for the duration of the study (31 days). Injection of anti-CD70CART cells lead to decreased tumor volumes at both doses (FIG. 37).These data show that anti-CD70 CART cells can regress CD70+ kidneycancer tumors in vivo.

Transgene insertion in primary human T cells via homology directedrepair (HDR) and concurrent gene knockout by Cas9:sgRNA RNA wasperformed as described above in Example 16 to produce cells lacking TCRsurface expression and to concurrently express an anti-CD70 CARconstruct (TRAC⁻/anti-CD70CAR+ cells). Primary human T cells were firstelectroporated with Cas9 or Cas9:sgRNA RNP complexes targeting TRAC(AGAGCAACAGTGCTGTGGCC (SEQ ID NO: 76); TRAC gRNA spacer(AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152)). The DNA double stranded breakat the TRAC locus was repaired by homology directed repair with anAAV6-delivered DNA template (CTX-145; SEQ ID NO: 1359) containing rightand left homology arms to the TRAC locus flanking a chimeric antigenreceptor cassette (−/+ regulatory elements for gene expression). Theresulting modified T cells are TRAC/anti-CD70CAR+. The ability of themodified TRAC⁻/anti-CD70CAR+ T cells to ameliorate disease caused by aCD70+ renal carcinoma cell line was evaluated in NOG mice using methodsemployed by Translational Drug Development, LLC (Scottsdale, Ariz.). Inbrief, twelve (12), 5-8 week old female, CIEA NOG(NOD.Cg-Prkdc^(scid)I12rg^(tm1Sug)/JicTac) mice were individually housedin ventilated microisolator cages, maintained under pathogen-freeconditions, 5-7 days prior to the start of the study. On Day 1 micereceived a subcutaneous inoculation of 5×10⁶ A498 renal carcinomacells/mouse. The mice were further divided into 3 treatment groups asshown in Table 26. On Day 10 (9 days post inoculation with the A498cells), treatment group 2 and group 3 received a single 200 μlintravenous dose of TRAC⁻/anti-CD70CAR+ cells according to Table 26.

TABLE 28 Treatment groups Group A498 cells T cell treatment (i.v.) N 1 5× 10⁶ cells/mouse None 8 2 5 × 10⁶ cells/mouse 1 × 10⁷ cells/mouse 3 3 5× 10⁶ cells/mouse 2 × 10⁷ cells/mouse 3

Tumor volumes were measured every 2 days. By Day 18 treatment with theanti-CD70 CART cells at both doses began to show a decrease in tumorvolume (FIG. 37). Tumor volume continues to decrease for the duration ofthe study. These data demonstrate that anti-CD70 CART cells can regressCD70+ kidney cancer tumors in vivo.

Example 26. —Anti-BCMA CAR Expression and Cytotoxicity

Allogeneic anti-BCMA CAR T cells were generated as described above.Anti-BCMA CAR expression was measured by determining the percent ofcells that bound biotinylated BCMA subsequently detected by FACS usingstreptavidin-APC (FIG. 47).

Anti-BCMA CAR constructs were then evaluated for their ability to killRPMI-8226 cells. All Anti-BCMA CAR T cells with ≥10% expression werepotently cytotoxic towards effector cells, while allogeneic T cellslacking a CAR showed little cytotoxicity (FIG. 48).

Example 27.—Cell Health Maintenance Post Gene Editing

Allogenic anti-CD19 CAR T cells were generated as described above. At 21days post gene editing, the following protocol was used to stain cellsfor expression of the indicated marker:

Stain cells with the following antibody for 30 min at 4° C.

Anti-mouse Fab2 biotin 115-065-006 (Jackson ImmunoRes) 1:5

Wash cells 1× with FACS buffer.

Add 1 μg of normal mouse IGG (Peprotech 500-M00) to 100 μL of cells for10 min at RT.

Wash cells 1× with FACS buffer and resuspend in 100 μL of FACS buffer.

Stain cells with the following cocktail for 15 min at RT.

The antibodies used in this Example are as follows:

TABLE 29 Antibody Clone Fluor Catalogue # Dilution For 1 CD4 RPA-T4BV510 300545 1:100 1 uL (Biolegend) CD8 SK1 BV605 344741 1:100 1 uL(Biolegend) CD45RA HI100 APC-CY7 304128 1:100 1 uL (Biolegend) CCR7G043H7 Pacific 353210 1:100 1 uL Blue (Biolegend) PD1 EH12.2H7 PE 3299061:100 1 uL (Biolegend) LAG3 11C3C65 PE-Cy7 369310 1:100 1 uL (Biolegend)CD57 HCD57 FITC 322306 1:100 1 uL (Biolegend) Streptavidin APC17-4317-82 1:100 1 uL (eBioscience)

This data shows that health of TRAC−/B2M−/anti-CD19+CAR T cells ismaintained at day 21 post gene editing (the cells behave as normal(unedited) cells).

Example 28.—Comparison of TCR Genotype in Gene Edited Cells Pre- andPost-Enrichment

TRAC−/B2M−/anti-CD19+CAR T cells (TC1) cells were produced and weredepleted using TCRab antibodies and the Prodigy System (MiltenyiBiotech). Purities of >99.5% TCRab⁻ cells in the total population wereachieved from starting inputs of 95.5% TCRab-cells.

Example 29. —Allogeneic Anti-BCMA CAR T Cell Targeting

This example demonstrates the generation of an allogeneic anti-BCMACAR−T cells using CRISPR/Cas9 genome editing. High efficiency editingwas attained with over 60% of the cells harboring the three desirededits. The CAR−T cells maintain a normal CD4/CD8 ratio, as well ascharacteristic cytokine dependency, suggesting neither abnormal tonicsignaling from CAR insertion nor transformation due to the editingprocess have occurred. The CAR−T cells selectively killed BCMA⁺ cellsand secreted T cell activation cytokines following encounter withBCMA-expressing cells. The CAR−T cells eradicated MM cells in asubcutaneous RPMI-8226 tumor xenograft model, confirming potent activityin vivo.

High Efficiency Genome Editing by CRISPR/Cas9

TRAC⁻/B2M⁻/anti-BCMA CAR+ cells were generated using the methodsdescribed in Example 19. FIG. 52A shows a FACS plot of β2M and TRACexpression one week following gene editing (left) and a representativeFACS plot of CAR expression following knock-in to the TRAC locus(right). FIG. 52B is a graph showing decreased surface expression ofboth TCR and MHC-I following gene editing. Combined with a high CARexpression, this leads to more than 60% cells with all desiredmodifications (TCR−/β2M−/anti-BCMA CAR+).

T Cell CD4+/CD8+ Ratio Following Editing

At two weeks post gene editing, the following protocol was used to stainTCR−/β2M−/anti-BCMA CAR+ cells for expression of the indicated marker:

Stain cells with the following antibody for 30 min at 4° C.

Recombinant biotinylated human BCMA (Acro Biosystems Cat: #BC7-H82F0 ata concentration of 100 nM

Wash cells 1× with FACS buffer and resuspend in 100 μL of FACS buffer.

Stain cells with the following cocktail for 15 min at RT.

The antibodies used in this Example were CD4 and CD8 (See Table 27).This data showed that the edited T cells had the same CD4+/CD8+ ratio asunedited T cells. (data not shown).

Two weeks following editing and anti-BCMA CAR knock-in, serum and/orcytokines were removed from the growth media. As expected, in theabsence of cytokines no further proliferation of T-cells was observed(FIG. 53). Additionally, T-cells showed reduced proliferation followingprolonged in vitro culture.

Allogeneic Anti-BCMA CAR T Cells Show Potent and Specific Activity InVitro

To assess the ability of TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells toselectively kill a BCMA expressing multiple myeloma cell line (MM.1S), aflow cytometry based cell killing assay was designed, similar to theassay described in Example 21. The TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells(see Example 19 for Table of CARs used) were co-cultured with cells ofthe BCMA-expressing MM.1S multiple myeloma cell line or cells of theK562 cell line, which do not express BCMA (collectively referred to asthe “target cells”).

Target cells per μL were then calculated from analyzed flow cytometrydata:Cells/μL=((number of live target cell events)/(number of beadevents))×((Assigned bead count of lot (beads/50 μL))/(volume of sample))

Total target cells were calculated by multiplying cells/μL×the totalvolume of cells.

The percent cell lysis was then calculated with the following equation:% Cell lysis=(1−((Total Number of Target Cells in Test Sample)/(TotalNumber of Target Cells in Control Sample))×100.

FIG. 54A shows that TRAC−/B2M−/anti-BCMA CAR+ T cells selectively killedMM.1S cells but showed no specific toxicity toward K562 cells (whichlack BCMA expression). The results indicate that the CRISPR/Cas9modified T cells described herein, induce potent cell lysis in aBCMA-expressing multiple myeloma cell line.

The ability of the engineered TRAC−/B2M−/anti-BCMA CAR+ T cells toproduce interferon gamma (IFNγ) and IL-2 in response to target cells wasanalyzed using an ELISA assay, as described above and in Examples, 10,18, and 21.

The specificity of genetically modified T cells expressing an anti-BCMACAR integrated into the TRAC gene, was evaluated in an in vitro ELISAassay. IFNγ and IL-2 from supernatants of cell co-cultures was measured.MM.1S cells were cultured with genetically engineered T cells expressingthe anti-BCMA CAR, or controls. FIG. 54B demonstrates thatTRAC⁻/B2M⁻/anti-BCMA CAR+ T cells (cells expressing CTX166) secretehigher levels of IFNγ and IL-2 when cultured with MM.1S cells ascompared to T cells that do not express the anti-BCMA CAR (unedited Tcells). By contrast, the TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells do notsecrete IFNγ or IL-2 when cultured with K562 cells (cells that do notexpress BCMA).

The cell kill assay was repeated with the addition of the multiplemyeloma cell line H929, which expresses higher levels of BCMA comparedto MM.1S (FIG. 54C). FIG. 54D shows that accelerated kill of the H929cells was observed compared to the MM1s cells (D). The cell killefficiency is shown using a ratio of 1:1 effector to T cell.

Thus, not only do the anti-BCMA CAR T cells of the present disclosureproduce IFNγ and IL-2, they do so specifically in the presence ofBCMA-expressing cells.

Allogeneic Anti-BCMA CAR T Cells Show Potent Activity In Vivo

In this example, the efficacy of CAR−T cells against the subcutaneousRPMI-8226 tumor xenograft model in NOG mice was evaluated. In brief, 12,5-8 week old female, CIEA NOG (NOD.Cg-Prkdc^(scid)I12rg^(tm1Sug)/JicTac)mice were individually housed in ventilated microisolator cages,maintained under pathogen-free conditions, 5-7 days prior to the startof the study. On Day 1 mice received a subcutaneous inoculation of10×10⁶ RPMI-8226 cells/mouse. The mice were further divided into twotreatment group. Ten (10) days post inoculation with RPMI-8226 cells,the first treatment group (N=5) received a single 200 μl intravenousdose of 10×10⁶ edited TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells, and the secondtreatment group (N=5) received a single 200 μl intravenous dose of20×10⁶ edited TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells.

Tumor volume and body weight was measured and individual mice wereeuthanized when tumor volume was ≥500 mm³. By Day 18, the data show astatistically significant decrease in the tumor volume in response toTRAC⁻/B2M⁻/anti-BCMA CAR+ T cells as compared to untreated mice (FIG.55).

PD1, B2M, TRAC Triple Knockout Anti-BCMA CAR−T Cells

This example describes the production by CRISPR/Cas9 and AAV6 ofallogeneic human T cells that lack expression of the TCR, MHC I, and PD1and express a chimeric antigen receptor targeting BCMA+ cancers.

CRISPR/Cas9 and AAV6 were used as above (see for example, Examples 8-10and 12) to create human T cells that lack expression of the TCR, B2M andPD1 with concomitant expression from the TRAC locus using a CARconstruct targeting BCMA (SEQ ID NO: 1434). In this example activated Tcells were electroporated with 3 distinct RNP complexes containingsgRNAs targeting TRAC (e.g., TRAC gRNA spacer SEQ ID NO: 152), B2M(e.g., B2M gRNA spacer SEQ ID NO: 466) and PD1 (e.g., PD1 gRNA spacerSEQ ID NO: 1086). About 1 week post electroporation cells were eitherleft untreated or treated with PMA/ionomycin overnight. The next daycells were processed for flow cytometry. FIG. 38 shows that only cellstreated with PD1 sgRNA containing RNP do not upregulate PD1 surfacelevels in response to an overnight treatment of PMA/ionomycyin.

Example 30. —Allogeneic Anti-CD70 CAR T Cell Targeting

High Efficiency CRISPR/Cas9 Gene Editing to Produce Allogeneic Anti-CD70CAR−T Cells

This example demonstrates efficient transgene insertion and concurrentgene knockout by Cas9:sgRNA RNP (for double stranded break induction)and AAV6 delivered donor template containing a CD70 CAR construct (SEQID NO: 1424) in primary human T cells. The experiments described hereare similar to those described in Example 16.

Primary human T cells were activated with CD3/CD28 magnetic beads (asdescribed previously in Example 2). Three days later activation beadswere removed. The next day cells were electroporated with RNP complexesincluding sgRNAs targeting either TRAC alone, or TRAC+ B2M (twoseparately complexed RNPs). Seven days post manipulation, cells wereanalyzed by flow cytometry, as previously described herein and inExample 2.

Guides used in this example target:

TRAC: (SEQ ID NO: 76) AGAGCAACAGTGCTGTGGCC; TRAC sgRNA (SEQ ID NO: 686)B2M: (SEQ ID NO: 417) GCTACTCTCTCTTTCTGGCC; TRAC sgRNA (SEQ ID NO: 688).

The gRNAs used in this Example comprise the following spacer sequences:TRAC gRNA spacer (AGAGCAACAGUGCUGUGGCC (SEQ ID NO: 152)); and B2M gRNAspacer (GCUACUCUCUCUUUCUGGCC (SEQ ID NO: 466)). FIG. 56A shows that highediting rates were achieved at the TRAC and β2M loci resulting indecreased surface expression of TCR and MHC-I. Highly efficientsite-specific integration and expression of the anti-CD70 CAR from theTRAC locus was also detected. Data are from three healthy donors. FIG.56B shows that production of allogeneic anti-CD70 CAR−T cells (TCR−β2M−CAR+) preserves CD4 and CD8 proportions.

Anti-CD70 CAR−T Cells Kill Multiple Myeloma Cells

To assess the ability of TRAC⁻/B2M⁻/anti-CD70 CAR+ T cells to kill aCD70− expressing multiple myeloma cell line (MM.1S), a flowcytometry-based cell killing assay was designed, similar to the assaydescribed in Examples 21 and 29. The TRAC⁻/B2M⁻/anti-CD70 CAR+ T cellswere co-cultured with cells of the BCMA-expressing MM.1s multiplemyeloma cell line. FIG. 57 shows that allogeneic anti-CD70 CAR−T cells(TCR−β2M− CAR+) show potent cytotoxicity against the CD70+ MM.1Smultiple myeloma-derived cell line.

Example 31. —Comparison of Anti-BCMA (CD28) CAR and Anti-BCMA (4-1BB)CAR

CAR Expression

Allogeneic TRAC−/B2M−/anti-BCMA CAR T+ cells were generated, asdescribed above, having either a CD28 co-stimulatory domain (encoded byCTX-160 or CTX-166) or a 4-1BB co-stimulatory domain (encoded by CTX160bor CTX166b). Anti-BCMA CAR expression was measured by determining thepercent of cells that bound biotinylated BCMA subsequently detected byFACS using streptavidin-APC (FIG. 67). Greater than 60% of the cellsexpressed the CAR at the cell surface.

Cytotoxicity

To assess the ability of the same TRAC⁻/B2M⁻/anti-BCMA (CD28 v. 4-1BB)CAR+ T cells to selectively kill a BCMA expressing multiple myeloma cellline (MM.1S), a flow cytometry based cell killing assay was designed,similar to the assay described in Example 21. The TRAC⁻/B2M⁻/anti-BCMACAR+ T cells were co-cultured with cells of the BCMA-expressing MM.1Smultiple myeloma cell line.

Target cells per μL were then calculated from analyzed flow cytometrydata:Cells/μL=((number of live target cell events)/(number of beadevents))×((Assigned bead count of lot (beads/50 μL))/(volume of sample))

Total target cells were calculated by multiplying cells/μL×the totalvolume of cells. The percent cell lysis was then calculated with thefollowing equation:% Cell lysis=(1−((Total Number of Target Cells in Test Sample)/(TotalNumber of Target Cells in Control Sample))×100.

FIG. 68 shows that all TRAC−/B2M−/anti-BCMA CAR+ T cells killed MM.1Scells. The results indicate that the CRISPR/Cas9 modified T cellsdescribed herein, induce potent cell lysis in a BCMA-expressing multiplemyeloma cell line.

Interferon Gamma Secretion

The ability of the engineered TRAC−/B2M−/anti-BCMA (CD28 v. 4-1BB) CAR+T cells to produce interferon gamma (IFNγ) in response to target cellswas analyzed using an ELISA assay, as described above and in Examples,10, 18, and 21.

The specificity of genetically modified T cells was evaluated in an invitro ELISA assay. IFNγ from supernatants of cell co-cultures wasmeasured. MM.1S cells were cultured with genetically engineered T cellsexpressing the anti-BCMA CAR, or controls. FIG. 69 demonstrates that allTRAC⁻/B2M⁻/anti-BCMA CAR+ T cells secrete higher levels of IFNγ whencultured with MM.1S cells as compared to T cells that do not express theanti-BCMA CAR (unedited T cells). By contrast, the TRAC⁻/B2M⁻/anti-BCMACAR+ T cells do not secrete IFNγ or IL-2 when cultured with K562 cells(cells that do not express BCMA).

Thus, not only do the anti-BCMA CAR T cells of the present disclosureproduce IFNγ, they do so specifically in the presence of BCMA-expressingcells.

Cell Kill Assay

To assess the ability of TRAC⁻/B2M⁻/anti-BCMA (4-1BB) CAR+ T cells tokill suspension cell lines, a flow cytometry-based cell killing assaywas designed. The TRAC⁻/B2M⁻/anti-BCMA CAR+ T cells were co-culturedwith cells of the BCMA-expressing RPMI-8226 (ATCC Cat #ATCC-155) humanplasmacytoma target cell line, cells of the BCMA-expressing U-266 cellline, cells of the multiple myeloma cell line H929, or cells of the K562cell line, which do not express BCMA (collectively referred to as the“target cells”. The target cells were labeled with 5 μM efluor670(eBiosciences), washed and incubated in co-cultures with theTRAC⁻/B2M⁻/anti-BCMA CAR+ T cells at varying ratios (from 0.1:1 to 8:1 Tcells to target cells) at 50,000 target cells per well of a U-bottom96-well plate overnight. The next day wells were washed, media wasreplaced with 200 μL of media containing a 1:500 dilution of 5 mg/mLDAPI (Molecular Probes) (to enumerate dead/dying cells). Finally, 25 μLof CountBright beads (Life Technologies) was added to each well. Cellswere then processed by flow cytometry.

Target cells per μL were then calculated from analyzed flow cytometrydata:Cells/μL=((number of live target cell events)/(number of beadevents))×((Assigned bead count of lot (beads/50 μL))/(volume of sample))

Total target cells were calculated by multiplying cells/μL×the totalvolume of cells. The percent cell lysis was then calculated with thefollowing equation:% Cell lysis=(1−((Total Number of Target Cells in Test Sample)/(TotalNumber of Target Cells in Control Sample))×100

FIG. 70 shows that TRAC−/B2M−/anti-BCMA (4-1BB) CAR+ T cells selectivelykilled RPMI 8226 cells, U-266 cells, and H929 cells, with no specifictoxicity toward K562 cells (which lack BCMA expression). The resultsindicate that the CRISPR/Cas9 modified T cells induce potent cell lysisin BCMA expressing plasmacytoma cell line.

Interferon Gamma and IL-2 Stimulation

The ability of the TRAC−/B2M−/anti-BCMA (4-1BB) CAR+ T cells to produceinterferon gamma (IFNγ) in a target cell was analyzed using an ELISAassay, as described above and in Example 10 and 18.

The specificity of genetically modified T cells expressing an anti-BCMACAR integrated into the TRAC gene, was evaluated in an in vitro ELISAassay. IFNγ and IL-2 from supernatants of cell co-cultures was measured.Target RPMI-8226, U2261, H929, or K562 cells were cultured withgenetically engineered T cells expressing the anti-BCMA CAR, orcontrols. FIGS. 73 and 74 demonstrates that TRAC⁻/B2M⁻/anti-BCMA CAR+ Tcells secrete higher levels of IFNγ (FIG. 71) and IL-2 (FIG. 72) whencultured with each of the target cell lines, as compared to T cells thatdo not express the anti-BCMA CAR (no RNP) (at a 0.5:1, 1:1, 1.5:1, 2:1,and 2.5:1 CAR−T cell to target ratio), with the exception of the K562cell line. Thus, not only do the TRAC−/B2M−/anti-BCMA (4-1BB) CAR+ Tcells of the present disclosure produce IFNγ and IL-2, they do sospecifically in the presence of BCMA-expressing cells.

Similar studies as above were repeated using TRAC−/B2M−/anti-BCMA(4-1BB) CAR+ T cells compared to TRAC−/B2M−/PD-1−/anti-BCMA (4-1BB) CAR+T cells. The edited cells were assayed with MM.1S cells or K562 cellsfor cytotoxicity, IFN-γ stimulation, and IL-2 stimulation. The resultsare depicted in FIG. 74, showing that the edited cells induce potentcell lysis specifically in the BCMA-expressing K562 cell line, and theyproduce IFNγ and IL-2 specifically in the presence of BCMA-expressingcells (FIG. 74).

Example 32—In Vivo Tumor Model for Anti-BCMA CAR in Context of PD-1Knockout

The efficacy of TRAC−/B2M−/anti-BCMA (CD28 co-stim) CAR+ T cells andTRAC−/B2M−/PD-1−/anti-BCMA (CD28 co-stim) CAR+ T cells against thesubcutaneous RPMI-8226 tumor xenograft model in NOG mice was evaluated.In brief, thirty five (35), 5-8 week old female, CIEA NOG(NOD.Cg-Prkdc^(scid)I12rg^(tm1Sug)/JicTac) mice were individually housedin ventilated microisolator cages, maintained under pathogen-freeconditions, 5-7 days prior to the start of the study. On Day 1 micereceived a subcutaneous inoculation of 10×10⁶ RPMI-8226 cells/mouse. Ten(10) days post inoculation with RPMI-8226 cells, the mice were dividedinto 6 treatment groups (N=5) and dosed as indicated in Table 30.

TABLE 30 Group CAR T Cell # of T Cells injected N 1 N/A N/A 4 2TRAC-/B2M-/PD1-/CTX160 1 × 10⁷ cells/mouse 4 3 TRAC-/B2M-/CTX160 1 × 10⁷cells/mouse 4 4 TRAC-/B2M-/CTX160 2 × 10⁷ cells/mouse N 5TRAC-/B2M-/PD1-/CTX166 1 × 10⁷ cells/mouse 4 6 TRAC-/B2M-/CTX166 1 × 10⁷cells/mouse 4 7 TRAC-/B2M-/CTX166 2 × 10⁷ cells/mouse 4

Tumor volume and body weight was measured and individual mice wereeuthanized when tumor volume was ≥500 mm³. By Day 18, the data show astatistically significant decrease in the tumor volume in response toTRAC−/B2M−/anti-BCMA (CD28 co-stim) CAR+ T cells andTRAC−/B2M−/PD-1−/anti-BCMA (CD28 co-stim) CAR+ T cells as compared tountreated mice (FIG. 73).

Example 33—Efficacy of TRAC−/B2M−/Anti-CD70 CAR+ T Cells orTRAC−/B2M−/PD1−/Anti-CD70 CAR+ T Cells, with CD28 or 41BB CostimulatoryDomains: The Subcutaneous Renal Cell Carcinoma Tumor Xenograft Model inNOG Mice

NOG mice were injected subcutaneously with 5×10⁶ A498 renal cellcarcinoma cells. When tumors reached ˜150 mm³, mice were either leftuntreated or injected intravenously (I.V.) with a therapeutic dose of1×10⁷ anti-CD70 CAR−T cells. Tumor volumes were measured every 2 daysfor the duration of the study. Injection of anti-CD70 CART cells lead todecreased tumor volumes (FIG. 75) before the tumors grow again. Thesedata show that TRAC−/B2M− or TRAC−/B2M−/PD1− anti-CD70 CAR+ T cells,with CD28 or 41BB costimulatory domains, have similar anti-tumoractivity against CD70+ kidney cancer tumors in vivo.

The anti-CD70 CAR+ T cells were generated as described above in Example18. Furthermore the in vivo study was conducted similarly to the onedescribed in Example 25. The ability of the modified TRAC⁻/B2M− orTRAC−/B2M−/PD1− anti-CD70CAR+ T cells, with CD28 or 41BB co-stimulatorydomains, to ameliorate disease caused by a CD70+ renal carcinoma cellline was evaluated in NOG mice using methods employed by TranslationalDrug Development, LLC (Scottsdale, Ariz.). In brief, 5-8 week oldfemales, CIEA NOG (NOD.Cg-Prkdc^(scid)I12rg^(tm1Sug)/JicTac) mice wereindividually housed in ventilated microisolator cages, maintained underpathogen-free conditions, 5-7 days prior to the start of the study. OnDay 1 mice received a subcutaneous inoculation of 5×10⁶ A498 renalcarcinoma cells/mouse. The mice were further divided into 5 treatmentgroups as shown in Table 31. When tumors reach ˜150 mm³, treatmentgroups 2, 3, 4 and 5 received a single 200 μl intravenous dose ofTRAC/anti-CD70CAR+ cells according to Table 31.

TABLE 31 Treatment groups T cell Group A498 cells treatment (i.v.) N 1 5× 10⁶ cells/mouse None 12 2. CD28, TRAC- B2M- 5 × 10⁶ cells/mouse 1 ×10⁷ 5 cells/mouse 3. CD28, TRAC- B2M- PD1- 5 × 10⁶ cells/mouse 1 × 10⁷ 5cells/mouse 4. 41BB, TRAC-, B2M- 5 × 10⁶ cells/mouse 1 × 10⁷ 5cells/mouse 5. 41BB, TRAC-, B2M-, PD1- 5 × 10⁶ cells/mouse 1 × 10⁷ 5

Tumor volumes were measured every 2 days. These data demonstrate thatTRAC−/B2M− or TRAC−/B2M−/PD1− anti-CD70 CAR+ T cells, with CD28 or 41BBcostimulatory domains, have similar anti-tumor activity against CD70+kidney cancer tumors in vivo.

FIG. 75 is a graph depicting similar decrease in tumor volume (mm³)following treatment of NOG mice that were injected subcutaneously withA498 renal cell carcinoma cell lines with TRAC−/B2M− or TRAC−/B2M−/PD1−anti-CD70 CAR+ T cells, with CD28 or 41BB costimulatory domains. AllGroups of NOG mice were injected with 5×10⁶ cells/mouse. Group 1received no T cell treatment. Mice in Group 2 were treated intravenouslywith 1×10⁷ cell/mouse of TRAC−/B2M− anti-CD70 CAR+ T cells, with CD28costimulatory domain, when tumors reached ˜150 mm³. Mice in Group 3 weretreated intravenously with 2×10⁷ cell/mouse of TRAC−/B2M−/PD1− anti-CD70CAR+ T cells, with CD28 costimulatory domain, when tumors reached ˜150mm³. Mice in Group 3 were treated intravenously with 1×10⁷ cell/mouse ofTRAC−/B2M− anti-CD70 CAR+ T cells, with 41BB costimulatory domain, whentumors reached ˜150 mm³. Mice in Group 4 were treated intravenously with2×10⁷ cell/mouse of TRAC−/B2M−/PD1− anti-CD70 CAR+ T cells, with 41BBcostimulatory domain, when tumors reached ˜150 mm³

TABLE 32 Modified sgRNAs SEQ IDSEQUENCE (*: indicates a nucleotide with a 2′-O′methyl NO: DESCRIPTIONphosphorothioate modification) 1342 TRAC modifiedA*G*A*GCAACAGUGCUGUGGCCGUUUUAGAGCUAGAAAUAGCAAG sgRNAUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGA GUCGGUGCU*U*U*U 1343 TRACAGAGCAACAGUGCUGUGGCCGUUUUAGAGCUAGAAAUAGCAAGUU unmodifiedAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGU sgRNA CGGUGCUUUU 1344B2M modified G*C*U*ACUCUCUCUUUCUGGCCGUUUUAGAGCUAGAAAUAGCAAG sgRNAUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGA GUCGGUGCU*U*U*U 1345B2M unmodified GCUACUCUCUCUUUCUGGCCGUUUUAGAGCUAGAAAUAGCAAGUU sgRNAAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGU CGGUGCUUUU 1346AAVS1 modified G*G*G*GCCACUAGGGACAGGAUGUUUUAGAGCUAGAAAUAGCAAG sgRNAUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGA GUCGGUGCU*U*U*U 1347 AAVS1GGGGCCACUAGGGACAGGAUGUUUUAGAGCUAGAAAUAGCAAGUU unmodifiedAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGU sgRNA CGGUGCUUUU 1574PD1 modified C*U*G*CAGCUUCUCCAACACAUGUUUUAGAGCUAGAAAUAGCAAG sgRNAUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGA GUCGGUGCU*U*U*U 1575PD1 unmodified CUGCAGCUUCUCCAACACAUGUUUUAGAGCUAGAAAUAGCAAGUU sgRNAAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGU CGGUGCUUUU 1587TRAC modified G*A*G*AAUCAAAAUCGGUGAAUGUUUUAGAGCUAGAAAUAGCAA sgRNAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCG AGUCGGUGCU*U*U*U 1588 TRACGAGAAUCAAAAUCGGUGAAUGUUUUAGAGCUAGAAAUAGCAAGU unmodifiedUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAG sgRNA UCGGUGCUUUU

TABLE 33 Constructs CAR CAR scFv scFv rAAV LHA to RHA Nucleotide AminoAcid Nucleotide Amino Acid Description Table 34 Table 35 Table 36 Table37 Table 38 Table 39 Name SEQ ID NOs. CTX-131 Anti-CD19 1348 1387 13161338 1333 1334 (GFP) CTX-132 Anti-CD19 1349 — 1316 1338 1333 1334 (GFP)CTX-133 Anti-CD19 1350 1388 1316 1338 1333 1334 (GFP) CTX-134 Anti-CD191351 — 1316 1338 1333 1334 (GFP) CTX-135 Anti-CD19 1352 1389 1316 13381333 1334 (GFP) CTX-136 Anti-CD19 1353 — 1316 1338 1333 1334 (GFP)CTX-138 Anti-CD19 1354 1390 1316 1338 1333 1334 (no GFP) CTX-139Anti-CD19 1355 1391 1316 1338 1333 1334 (no GFP) CTX-139.1 Anti-CD191583 1316 1338 1333 1334 (no GFP) CTX-139.2 Anti-CD19 1584 1316 13381333 1334 (no GFP) CTX-139.3 Anti-CD19 1585 1316 1338 1333 1334 (no GFP)CTX-140 Anti-CD19 1356 1392 1316 1338 1333 1334 (no GFP) CTX-141Anti-CD19 1357 1393 1316 1338 1333 1334 (no GFP) CTX-142 Anti-CD70 13581394 1423 1449 1475 1499 (CD70A, no GFP) CTX-145 Anti-CD70 1359 13951424 1450 1476 1500 (CD70B, no GFP) CTX-145b Anti-CD70 1360 1396 12751276 1476 1500 (4-1BB) CTX-152 Anti-BCMA 1361 1397 1425 1451 1477 1501(BCMA-1, GFP) CTX-153 Anti-BCMA 1362 1398 1425 1451 1477 1501 (BCMA-1,no GFP) CTX-154 Anti-BCMA 1363 1399 1426 1452 1478 1502 (BCMA-2, GFP)CTX-155 Anti-BCMA 1364 1400 1426 1452 1478 1502 (BCMA-2, no GFP) CTX-160Anti-BCMA 1365 1401 1427 1453 1479 1503 CTX-160b Anti-BCMA 1366 14021428 1454 1479 1503 (4-1BB) CTX-161 Anti-BCMA 1367 1403 1429 1455 14801504 CTX-162 Anti-BCMA 1368 1404 1430 1456 1481 1505 CTX-163 Anti-BCMA1369 1405 1431 1457 1482 1506 CTX-164 Anti-BCMA 1370 1406 1432 1458 14831507 CTX-165 Anti-BCMA 1371 1407 1433 1459 1484 1508 CTX-166 Anti-BCMA1372 1408 1434 1460 1485 1509 CTX-166b Anti-BCMA 1373 1409 1435 14611485 1509 (4-1BB) CTX-167 Anti-BCMA 1374 1410 1436 1462 1486 1510CTX-168 Anti-BCMA 1375 1411 1437 1463 1487 1511 CTX-169 Anti-BCMA 13761412 1438 1464 1488 1512 CTX-170 Anti-BCMA 1377 1413 1439 1465 1489 1513CTX-171 Anti-BCMA 1378 1414 1440 1466 1490 1514 CTX-172 Anti-BCMA 13791415 1441 1467 1491 1515 CTX-173 Anti-BCMA 1380 1416 1442 1468 1492 1516CTX-174 Anti-BCMA 1381 1417 1443 1469 1493 1517 CTX-175 Anti-BCMA 13821418 1444 1470 1494 1518 CTX-176 Anti-BCMA 1383 1419 1445 1471 1495 1519CTX-177 Anti-BCMA 1384 1420 1446 1472 1496 1520 CTX-178 Anti-BCMA 13851421 1447 1473 1497 1521 CTX-179 Anti-BCMA 1386 1422 1448 1474 1498 1522

TABLE 34 rAAV Sequences SEQ ID NO: Description Sequence 1348 CTX-131CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAAGCCCAGAGCAGGGCCTTAGGGAAGCGGGACCCTGCTCTGGGCGGAGGAATATGTCCCAGATAGCACTGGGGACTCTTTAAGGAAAGAAGGATGGAGAAAGAGAAAGGGAGTAGAGGCGGCCACGACCTGGTGAACACCTAGGACGCACCATTCTCACAAAGGGAGTTTTCCACACGGACACCCCCCTCCTCACCACAGCCCTGCCAGGACGGGGCTGGCTACTGGCCTTATCTCACAGGTAAAACTGACGCACGGAGGAACAATATAAATTGGGGACTAGAAAGGTGAAGAGCCAAAGTTAGAACTCAGGACCAACTTATTCTGATTTTGTTTTTCCAAACTGCTTCTCCTCTTGGGAAGTGTAAGGAAGCTGCAGCACCAGGATCAGTGAAACGCACCAGACGGCCGCGTCAGAGCAGCTCAGGTTCTGGGAGAGGGTAGCGCAGGGTGGCCACTGAGAACCGGGCAGGTCACGCATCCCCCCCTTCCCTCCCACCCCCTGCCAAGCTCTCCCTCCCAGGATCCTCTCTGGCTCCATCGTAAGCAAACCTTAGAGGTTCTGGCAAGGAGAGAGATGGCTCCAGGAAATGGGGGTGTGTCACCAGATAAGGAATCTGCCTAACAGGAGGTGGGGGTTAGACCCAATATCAGGAGACTAGGAAGGAGGAGGCCTAAGGATGGGGCTTTTCTGTCACCAGCCACTAGTGGCCGCCAGTGTGATGGATATCTGCAGAATTCGCCCTTATGGGGATCCGAACAGAGAGACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGTTGGAACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGATGGTCCCCAGATGCGGTCCCGCCCTCAGCAGTTTCTAGAGAACCATCAGATGTTTCCAGGGTGCCCCAAGGACCTGAAATGACCCTGTGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCGCGCTTCTGCTCCCCGAGCTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGACTCTAGAGGGACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGACTGTGGGGTGGAGGGGACAGATAAAAGTACCCAGAACCAGAGCCACATTAACCGGCCCTGGGAATATAAGGTGGTCCCAGCTCGGGGACACAGGATCCCTGGAGGCAGCAAACATGCTGTCCTGAAGTGGACATAGGGGCCCGGGTTGGAGGAAGAAGACTAGCTGAGCTCTCGGACCCCTGGAAGATGCCATGACAGGGGGCTGGAAGAGCTAGCACAGACTAGAGAGGTAAGGGGGGTAGGGGAGCTGCCCAAATGAAAGGAGTGAGAGGTGACCCGAATCCACAGGAGAACGGGGTGTCCAGGCAAAGAAAGCAAGAGGATGGAGAGGTGGCTAAAGCCAGGGAGACGGGGTACTTTGGGGTTGTCCAGAAAAACGGTGATGATGCAGGCCTACAAGAAGGGGAGGCGGGACGCAAGGGAGACATCCGTCGGAGAAGGCCATCCTAAGAAACGAGAGATGGCACAGGCCCCAGAAGGAGAAGGAAAAGGGAACCCAGCGAGTGAAGACGGCATGGGGTTGGGTGAGGGAGGAGAGATGCCCGGAGAGGACCCAGACACGGGGAGGATCCGCTCAGAGGACATCACGTGGTGCAGCGCCGAGAAGGAAGTGCTCCGGAAAGAGCATCCTTGGGCAGCAACACAGCAGAGAGCAAGGGGAAGAGGGAGTGGAGGAAGACGGAACCTGAAGGAGGCGGCGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGC GCAGCTGCCTGCAGG 1349 CTX-132CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTACTAGTGGCCGCCAGTGTGATGGATATCTGCAGAATTCGCCCTTATGGGGATCCGAACAGAGAGACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGTTGGAACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGATGGTCCCCAGATGCGGTCCCGCCCTCAGCAGTTTCTAGAGAACCATCAGATGTTTCCAGGGTGCCCCAAGGACCTGAAATGACCCTGTGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCGCGCTTCTGCTCCCCGAGCTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGACTCTAGAGGGACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCG CAGCTGCCTGCAGG 1350 CTX-133CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1351 CTX-134CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1352 CTX-135CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTTTTGTAAAGAATATAGGTAAAAAGTGGCATTTTTTCTTTGGATTTAATTCTTATGGATTTAAGTCAACATGTATTTTCAAGCCAACAAGTTTTGTTAATAAGATGGCTGCACCCTGCTGCTCCATGCCAGATCCACCACACAGAAAGCAAATGTTCAGTGCATCTCCCTCTTCCTGTCAGAGCTTATAGAGGAAGGAAGACCCCGCAATGTGGAGGCATATTGTATTACAATTACTTTTAATGGCAAAAACTGCAGTTACTTTTGTGCCAACCTACTACATGGTCTGGACAGCTAAATGTCATGTATTTTTCATGGCCCCTCCAGGTATTGTCAGAGTCCTCTTGTTTGGCCTTCTAGGAAGGCTGTGGGACCCAGCTTTCTTCAACCAGTCCAGGTGGAGGCCTCTGCCTTGAACGTTTCCAAGTGAGGTAAAACCCGCAGGCCCAGAGGCCTCTCTACTTCCTGTGTGGGGTTCAGAAACCCTCCTCCCCTCCCAGCCTCAGGTGCCTGCTTCAGAAAATGGTGAGTCTCTCTCTTATAAAGCCCTCCTTTTTCATCCTAGCATTGGGAACAATGGCCCCAGGGTCCTTATCTCTAGCAGATGTTTTGAAAAAGTCATCTGTTTTGCTTTTTTTCCAGAAGTAGTAAGTCTGCTGGCCTCCGCCATCTTAGTAAAGTAACAGTCCCATGAAACAAAGATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGGTGAGTAGGATGGAGTGGAAAGGGTGGTGTGTCTCCAGACCGCTGGAAGGCTTACAGCCTTACCTGGCACTGCCTAGTGGCACCAAGGAGCCTCATTTACCAGATGTAAGGAACTGTTTGTGCTATGTTAGGGTGAGGGATTAGAGCTGGGGACTAAAGAAAAAGATAGGCCACGGGTGCCTGGGAGAGCGTTCGGGGAGCAGGCAAAGAAGAGCAGTTGGGGTGATCATAGCTATTGTGAGCAGAGAGGTCTCGCTACCTCTAAGTACGAGCTCATTCCAACTTACCCAGCCCTCCAGAACTAACCCAAAAGAGACTGGAAGAGCGAAGCTCCACTCCTTGTTTTGAAGAGACCAGATACTTGCGTCCAAACTCTGCACAGGGCATATATAGCAATTCACTATCTTTGAGACCATAAAACGCCTCGTAATTTTTAGTCCTTTTCAAGTGACCAACAACTTTCAGTTTATTTCATTTTTTTGAAGCAAGATGGATTATGAATTGATAAATAACCAAGAGCATTTCTGTATCTCATATGAGATAAATAATACCAAAAAAAGTTGCCATTTATTGTCAGATACTGTGTAAAGAAAAAATTATTTAGACGTGTTAACTGGTTTAATCCTACTTCTGCCTAGGAAGGAAGGTGTTATATCCTCTTTTTAAAATTCTTTTTAATTTTGACTATATAAACTGATAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1353 CTX-136CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGA GCGAGCGCGCAGCTGCCTGCAGG 1354CTX-138 CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGC CTGCAGG 1355 CTX-139CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGC GCAGCTGCCTGCAGG 1356 CTX-140TTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTAATCCTCCGGCAAACCTCTGTTTCCTCCTCAAAAGGCAGGAGGTCGGAAAGAATAAACAATGAGAGTCACATTAAAAACACAAAATCCTACGGAAATACTGAAGAATGAGTCTCAGCACTAAGGAAAAGCCTCCAGCAGCTCCTGCTTTCTGAGGGTGAAGGATAGACGCTGTGGCTCTGCATGACTCACTAGCACTCTATCACGGCCATATTCTGGCAGGGTCAGTGGCTCCAACTAACATTTGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATGGAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGGAAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGAGAAGAGCAGCAGGCATGAGTTGAATGAAGGAGGCAGGGCCGGGTCACAGGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCA A 1357 CTX-141CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTAATCCTCCGGCAAACCTCTGTTTCCTCCTCAAAAGGCAGGAGGTCGGAAAGAATAAACAATGAGAGTCACATTAAAAACACAAAATCCTACGGAAATACTGAAGAATGAGTCTCAGCACTAAGGAAAAGCCTCCAGCAGCTCCTGCTTTCTGAGGGTGAAGGATAGACGCTGTGGCTCTGCATGACTCACTAGCACTCTATCACGGCCATATTCTGGCAGGGTCAGTGGCTCCAACTAACATTTGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATGGAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGGAAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGAGAAGAGCAGCAGGCATGAGTTGAATGAAGGAGGCAGGGCCGGGTCACAGGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCT GCAGG 1358 CTX-142CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGATATAGTTATGACCCAATCACCCGATAGTCTTGCGGTAAGCCTGGGGGAGCGAGCAACAATAAACTGTCGGGCATCAAAATCCGTCAGTACAAGCGGGTATTCATTCATGCACTGGTATCAACAGAAACCCGGTCAGCCACCCAAGCTCCTGATTTATCTTGCGTCTAATCTTGAGTCCGGCGTCCCAGACCGGTTTTCCGGCTCCGGGAGCGGCACGGATTTTACTCTTACTATTTCTAGCCTTCAGGCCGAAGATGTGGCGGTATACTACTGCCAGCATTCAAGGGAAGTTCCTTGGACGTTCGGTCAGGGCACGAAAGTGGAAATTAAAGGCGGGGGGGGATCCGGCGGGGGAGGGTCTGGAGGAGGTGGCAGTGGTCAGGTCCAACTGGTGCAGTCCGGGGCAGAGGTAAAAAAACCCGGCGCGTCTGTTAAGGTTTCATGCAAGGCCAGTGGATATACTTTCACCAATTACGGAATGAACTGGGTGAGGCAGGCCCCTGGTCAAGGCCTGAAATGGATGGGATGGATAAACACGTACACCGGTGAACCTACCTATGCCGATGCCTTTAAGGGTCGGGTTACGATGACGAGAGACACCTCCATATCAACAGCCTACATGGAGCTCAGCAGATTGAGGAGTGACGATACGGCAGTCTATTACTGTGCAAGAGACTACGGCGATTATGGCATGGATTACTGGGGCCAGGGCACTACAGTAACCGTTTCCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCT GCCTGCAGG 1359 CTX-145CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTCCAGTTGGTGCAAAGCGGGGCGGAGGTGAAAAAACCCGGCGCTTCCGTGAAGGTGTCCTGTAAGGCGTCCGGTTATACGTTCACGAACTACGGGATGAATTGGGTTCGCCAAGCGCCGGGGCAGGGACTGAAATGGATGGGGTGGATAAATACCTACACCGGCGAACCTACATACGCCGACGCTTTTAAAGGGCGAGTCACTATGACGCGCGATACCAGCATATCCACCGCATACATGGAGCTGTCCCGACTCCGGTCAGACGACACGGCTGTCTACTATTGTGCTCGGGACTATGGCGATTATGGCATGGACTACTGGGGTCAGGGTACGACTGTAACAGTTAGTAGTGGTGGAGGCGGCAGTGGCGGGGGGGGAAGCGGAGGAGGGGGTTCTGGTGACATAGTTATGACCCAATCCCCAGATAGTTTGGCGGTTTCTCTGGGCGAGAGGGCAACGATTAATTGTCGCGCATCAAAGAGCGTTTCAACGAGCGGATATTCTTTTATGCATTGGTACCAGCAAAAACCCGGACAACCGCCGAAGCTGCTGATCTACTTGGCTTCAAATCTTGAGTCTGGGGTGCCGGACCGATTTTCTGGTAGTGGAAGCGGAACTGACTTTACGCTCACGATCAGTTCACTGCAGGCTGAGGATGTAGCGGTCTATTATTGCCAGCACAGTAGAGAAGTCCCCTGGACCTTCGGTCAAGGCACGAAAGTAGAAATTAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCT GCCTGCAGG 1360 CTX-145bCCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTCCAGTTGGTGCAAAGCGGGGCGGAGGTGAAAAAACCCGGCGCTTCCGTGAAGGTGTCCTGTAAGGCGTCCGGTTATACGTTCACGAACTACGGGATGAATTGGGTTCGCCAAGCGCCGGGGCAGGGACTGAAATGGATGGGGTGGATAAATACCTACACCGGCGAACCTACATACGCCGACGCTTTTAAAGGGCGAGTCACTATGACGCGCGATACCAGCATATCCACCGCATACATGGAGCTGTCCCGACTCCGGTCAGACGACACGGCTGTCTACTATTGTGCTCGGGACTATGGCGATTATGGCATGGACTACTGGGGTCAGGGTACGACTGTAACAGTTAGTAGTGGTGGAGGCGGCAGTGGCGGGGGGGGAAGCGGAGGAGGGGGTTCTGGTGACATAGTTATGACCCAATCCCCAGATAGTTTGGCGGTTTCTCTGGGCGAGAGGGCAACGATTAATTGTCGCGCATCAAAGAGCGTTTCAACGAGCGGATATTCTTTTATGCATTGGTACCAGCAAAAACCCGGACAACCGCCGAAGCTGCTGATCTACTTGGCTTCAAATCTTGAGTCTGGGGTGCCGGACCGATTTTCTGGTAGTGGAAGCGGAACTGACTTTACGCTCACGATCAGTTCACTGCAGGCTGAGGATGTAGCGGTCTATTATTGCCAGCACAGTAGAGAAGTCCCCTGGACCTTCGGTCAAGGCACGAAAGTAGAAATTAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGA GCGCGCAGCTGCCTGCAGG 1361CTX-152 CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTGCTTCATGCTGCTAGACCTCAGGTGCAGTTACAACAGTCAGGAGGAGGATTAGTGCAGCCAGGAGGATCTCTGAAACTGTCTTGTGCCGCCAGCGGAATCGATTTTAGCAGGTACTGGATGTCTTGGGTGAGAAGAGCCCCTGGAAAAGGACTGGAGTGGATCGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGTCTTCTGGAGGAGGAGGATCCGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGAGATATTGTGATGACACAAAGCCAGCGGTTCATGACCACATCTGTGGGCGACAGAGTGAGCGTGACCTGTAAAGCTTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCCAGACAGAGCCCTAAAGCCCTGATCTTTTCTGCCAGCCTGAGATTTTCTGGCGTTCCTGCCAGATTTACCGGCTCTGGCTCTGGCACCGATTTTACACTGACCATCAGCAATCTGCAGTCTGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAACTACCCCCTGACCTTTGGAGCTGGCACAAAACTGGAGCTGAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1362 CTX-153CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTGCTTCATGCTGCTAGACCTCAGGTGCAGTTACAACAGTCAGGAGGAGGATTAGTGCAGCCAGGAGGATCTCTGAAACTGTCTTGTGCCGCCAGCGGAATCGATTTTAGCAGGTACTGGATGTCTTGGGTGAGAAGAGCCCCTGGAAAAGGACTGGAGTGGATCGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGTCTTCTGGAGGAGGAGGATCCGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGAGATATTGTGATGACACAAAGCCAGCGGTTCATGACCACATCTGTGGGCGACAGAGTGAGCGTGACCTGTAAAGCTTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCCAGACAGAGCCCTAAAGCCCTGATCTTTTCTGCCAGCCTGAGATTTTCTGGCGTTCCTGCCAGATTTACCGGCTCTGGCTCTGGCACCGATTTTACACTGACCATCAGCAATCTGCAGTCTGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAACTACCCCCTGACCTTTGGAGCTGGCACAAAACTGGAGCTGAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGC GCAGCTGCCTGCAGG 1363 CTX-154CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTGCTTCATGCTGCTAGACCTGACATCGTGATGACCCAAAGCCAGAGGTTCATGACCACATCTGTGGGCGATAGAGTGAGCGTGACCTGTAAAGCCTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCTAGACAGAGCCCTAAAGCCCTGATCTTTAGCGCCAGCCTGAGATTTAGCGGAGTTCCTGCCAGATTTACCGGAAGCGGATCTGGAACCGATTTTACACTGACCATCAGCAACCTGCAGAGCGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAATTACCCTCTGACCTTTGGAGCCGGCACAAAGCTGGAGCTGAAAGGAGGAGGAGGATCTGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGACAAGTTCAATTACAGCAATCTGGAGGAGGACTGGTTCAGCCTGGAGGAAGCCTGAAGCTGTCTTGTGCCGCTTCTGGAATCGATTTTAGCAGATACTGGATGAGCTGGGTGAGAAGAGCCCCTGGCAAAGGACTGGAGTGGATTGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1364 CTX-155CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTGCTTCATGCTGCTAGACCTGACATCGTGATGACCCAAAGCCAGAGGTTCATGACCACATCTGTGGGCGATAGAGTGAGCGTGACCTGTAAAGCCTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCTAGACAGAGCCCTAAAGCCCTGATCTTTAGCGCCAGCCTGAGATTTAGCGGAGTTCCTGCCAGATTTACCGGAAGCGGATCTGGAACCGATTTTACACTGACCATCAGCAACCTGCAGAGCGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAATTACCCTCTGACCTTTGGAGCCGGCACAAAGCTGGAGCTGAAAGGAGGAGGAGGATCTGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGACAAGTTCAATTACAGCAATCTGGAGGAGGACTGGTTCAGCCTGGAGGAAGCCTGAAGCTGTCTTGTGCCGCTTCTGGAATCGATTTTAGCAGATACTGGATGAGCTGGGTGAGAAGAGCCCCTGGCAAAGGACTGGAGTGGATTGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGC GCGCAGCTGCCTGCAGG 1365CTX-160 CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTCCAGCTGGTGGAGAGCGGCGGAGGACTGGTCCAGCCTGGCGGCTCCCTGAAACTGAGCTGCGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAATGGATCGGCGAGATCAACCCCGACTCCAGCACCATCAACTACGCCGACAGCGTCAAGGGCAGGTTCACCATTAGCAGGGACAATGCCAAGAACACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAAGACACCGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCTCCGGAGGAGGCGGCAGCGGCGGAGGCGGCAGCGGCGGAGGCGGCAGCGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCTCCGTGGGAGATAGGGTGACAATCACCTGTAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTATCAACAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTTTCCGCCTCCCTGAGGTTCAGCGGAGTCCCCAGCAGGTTCTCCGGATCCGGCTCCGGAACCGACTTTACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAGCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGC CTGCAGG 1366 CTX-160bCCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTCCAGCTGGTGGAGAGCGGCGGAGGACTGGTCCAGCCTGGCGGCTCCCTGAAACTGAGCTGCGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAATGGATCGGCGAGATCAACCCCGACTCCAGCACCATCAACTACGCCGACAGCGTCAAGGGCAGGTTCACCATTAGCAGGGACAATGCCAAGAACACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAAGACACCGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCTCCGGAGGAGGCGGCAGCGGCGGAGGCGGCAGCGGCGGAGGCGGCAGCGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCTCCGTGGGAGATAGGGTGACAATCACCTGTAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTATCAACAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTTTCCGCCTCCCTGAGGTTCAGCGGAGTCCCCAGCAGGTTCTCCGGATCCGGCTCCGGAACCGACTTTACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAGCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGC TGCCTGCAGG 1367 CTX-161CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCAGCCCGGAGGCTCCCTGAAGCTGAGCTGCGCTGCCTCCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGGCAGGCTCCCGGCAAAGGCCTGGAGTGGATCGGCGAGATCAACCCCGACAGCAGCACCATCAACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAATACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAGGACACAGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGAGACGCTATGGACTACTGGGGCCAGGGAACCCTGGTGACCGTGAGCAGCGGAGGCGGAGGCTCCGGCGGCGGAGGCAGCGGAGGAGGCGGCAGCGATATCCAGATGACCCAGTCCCCCAGCTCCCTGAGCGCTAGCCCTGGCGACAGGGTGAGCGTGACATGCAAGGCCAGCCAGAGCGTGGACAGCAACGTGGCCTGGTACCAGCAGAAACCCAGACAGGCCCCCAAGGCCCTGATCTTCAGCGCCAGCCTGAGGTTTAGCGGCGTGCCCGCTAGGTTTACCGGATCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCAACCTGCAGTCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAACTACCCCCTGACATTCGGCGCCGGAACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCT GCCTGCAGG 1368 CTX-162CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCTAGCGTGGGCGACAGGGTGACCATCACCTGCAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTACCAGCAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTCAGCGCCAGCCTGAGGTTCTCCGGAGTGCCTAGCAGATTTAGCGGCAGCGGCAGCGGCACAGACTTCACCCTGACCATCAGCAGCCTCCAGCCCGAGGATTTCGCCACCTACTACTGCCAGCAGTACAACTCCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGGGAGGAGGAGGAAGCGGAGGAGGAGGAAGCGGAGGCGGAGGAAGCGAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGCAACCTGGAGGCAGCCTGAAGCTGAGCTGTGCCGCCAGCGGAATCGACTTCAGCAGGTACTGGATGTCCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAGTGGATCGGAGAGATCAACCCCGACAGCTCCACCATCAACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGAGACAACGCCAAGAACACCCTGTACCTGCAGATGAACCTGTCCAGAGCCGAGGACACCGCCCTGTACTACTGCGCCAGCCTGTATTACGACTACGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGC CTGCAGG 1369 CTX-163CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCCAAATGACCCAGTCCCCTAGCAGCCTGTCCGCCAGCCCTGGAGACAGGGTGTCCGTGACCTGCAAGGCCAGCCAGTCCGTGGACAGCAACGTCGCCTGGTATCAGCAGAAGCCCAGGCAAGCTCCCAAGGCTCTGATCTTCTCCGCCAGCCTGAGATTTTCCGGCGTGCCCGCCAGATTCACCGGAAGCGGCAGCGGCACCGACTTCACCCTGACCATCAGCAACCTGCAGAGCGAGGATTTCGCCACATACTACTGCCAGCAGTACAACAACTACCCCCTGACCTTCGGAGCCGGCACCAAGCTGGAGATCAAAGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGATCCGAAGTGCAGCTGGTGGAAAGCGGAGGCGGACTCGTGCAGCCTGGCGGAAGCCTGAAGCTGAGCTGTGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGGCAGGCTCCCGGCAAAGGCCTGGAGTGGATCGGCGAGATCAACCCTGACAGCAGCACCATCAACTACGCCGACAGCGTGAAAGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACACCCTGTACCTGCAGATGAACCTGTCCAGAGCCGAGGACACCGCCCTGTACTACTGCGCCAGCCTGTACTACGACTACGGCGACGCTATGGACTACTGGGGCCAAGGCACCCTCGTGACCGTCAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGC CTGCAGG 1370 CTX-164CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTGCAGCTGCAGCAGTCCGGCCCTGAGCTCGTGAAGCCTGGAGCCAGCGTGAAAATGAGCTGTAAGGCCTCCGGCAACACCCTCACCAACTACGTGATCCATTGGATGAAGCAGATGCCCGGCCAGGGCCTGGACTGGATTGGCTACATTCTGCCCTACAACGACCTGACCAAGTACAACGAGAAGTTCACCGGCAAGGCCACCCTGACCAGCGATAAGAGCTCCAGCAGCGCCTACATGGAGCTGAACTCCCTGACCAGCGAGGACAGCGCCGTGTACTACTGCACCAGGTGGGACTGGGATGGCTTCTTCGACCCCTGGGGACAGGGCACCACCCTGACAGTGTCCAGCGGAGGAGGCGGCAGCGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGATATCGTGATGACACAGTCCCCTCTGAGCCTGCCTGTGAGCCTGGGCGACCAGGCCAGCATCAGCTGCAGGTCCACCCAGTCCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTACCTGCAAAGGCCCGGCCAGTCCCCTAAGCTGCTGATCTACAGCGTGAGCAACAGGTTTAGCGAGGTGCCCGATAGATTTTCCGCCAGCGGCAGCGGCACCGACTTCACACTGAAGATCTCCAGGGTGGAGGCCGAGGATCTGGGCGTGTACTTCTGCAGCCAGACCAGCCACATCCCCTACACCTTCGGCGGCGGAACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCA GCTGCCTGCAGG 1371 CTX-165CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCGTGATGACCCAGAGCCCCCTGAGCCTGCCTGTGTCCCTGGGAGACCAGGCTTCCATCAGCTGCAGGTCCACCCAGAGCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTACCTGCAGAGGCCTGGCCAGTCCCCCAAGCTGCTGATCTACAGCGTGAGCAATAGGTTCAGCGAGGTGCCCGACAGATTCAGCGCCAGCGGAAGCGGCACCGACTTCACCCTGAAGATCAGCAGGGTCGAGGCCGAAGATCTGGGCGTGTACTTCTGCTCCCAGACATCCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATTAAGGGCGGCGGAGGATCCGGCGGAGGAGGATCCGGAGGAGGAGGAAGCGAGGTGCAGCTGCAGCAGAGCGGACCCGAGCTGGTGAAACCCGGAGCCAGCGTCAAAATGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTCATCCACTGGATGAAGCAGATGCCCGGACAGGGCCTGGACTGGATCGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAACGAGAAATTCACCGGCAAGGCCACCCTGACCAGCGACAAGAGCAGCAGCAGCGCCTACATGGAGCTGAACAGCCTGACCAGCGAGGACTCCGCCGTGTACTATTGCACCAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACACTCACCGTGAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGC GCAGCTGCCTGCAGG 1372 CTX-166CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGGAGCCGAGCTCAAGAAGCCCGGAGCCTCCGTGAAGGTGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAAGCCCCCGGCCAAAGGCTGGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCTCCACCGCCTATATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGTACAAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACAGTGACCGTCAGCAGCGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGAAGCGAAATCGTGATGACCCAGAGCCCCGCCACACTGAGCGTGAGCCCTGGCGAGAGGGCCAGCATCTCCTGCAGGGCTAGCCAAAGCCTGGTGCACAGCAACGGCAACACCCACCTGCACTGGTACCAGCAGAGACCCGGACAGGCTCCCAGGCTGCTGATCTACAGCGTGAGCAACAGGTTCTCCGAGGTGCCTGCCAGGTTTAGCGGCAGCGGAAGCGGCACCGACTTTACCCTGACCATCAGCAGCGTGGAGTCCGAGGACTTCGCCGTGTATTACTGCAGCCAGACCAGCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGC GCAGCTGCCTGCAGG 1373CTX-166b CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGGAGCCGAGCTCAAGAAGCCCGGAGCCTCCGTGAAGGTGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAAGCCCCCGGCCAAAGGCTGGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCTCCACCGCCTATATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGTACAAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACAGTGACCGTCAGCAGCGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGAAGCGAAATCGTGATGACCCAGAGCCCCGCCACACTGAGCGTGAGCCCTGGCGAGAGGGCCAGCATCTCCTGCAGGGCTAGCCAAAGCCTGGTGCACAGCAACGGCAACACCCACCTGCACTGGTACCAGCAGAGACCCGGACAGGCTCCCAGGCTGCTGATCTACAGCGTGAGCAACAGGTTCTCCGAGGTGCCTGCCAGGTTTAGCGGCAGCGGAAGCGGCACCGACTTTACCCTGACCATCAGCAGCGTGGAGTCCGAGGACTTCGCCGTGTATTACTGCAGCCAGACCAGCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGA GCGAGCGAGCGCGCAGCTGCCTGCAGG1374 CTX-167 CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGGCGCCGAGCTGAAGAAACCTGGCGCCAGCGTCAAGGTGAGCTGCAAGGCTTCCGGAAACACCCTCACCAACTACGTGATCCACTGGGTGAGGCAGGCCCCCGGACAGAGACTGGAGTGGATGGGCTACATTCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTCACCATCACCAGGGACAAGAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGTCCGAGGACACAGCCGTGTACTACTGCACCAGGTGGGACTGGGACGGATTCTTCGACCCTTGGGGCCAAGGCACCACAGTGACAGTGAGCTCCGGCGGAGGCGGCAGCGGCGGCGGAGGAAGCGGCGGCGGCGGAAGCGACATCGTGATGACCCAGAGCCCTCTGAGCCTGCCCGTGACACTGGGACAGCCTGCCACACTGTCCTGCAGGAGCACCCAGAGCCTGGTGCATAGCAACGGCAACACCCACCTGCACTGGTTCCAGCAGAGACCTGGCCAGAGCCCCCTGAGACTGATCTACAGCGTGAGCAACAGGGACAGCGGCGTGCCCGATAGATTTAGCGGCAGCGGCAGCGGCACCGACTTTACCCTGAAAATCTCCAGGGTGGAGGCCGAGGATGTGGGCGTGTATTACTGCTCCCAGACAAGCCACATTCCCTATACATTCGGCGGCGGCACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGC GCGCAGCTGCCTGCAGG 1375CTX-168 CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAAATCGTGATGACCCAGAGCCCTGCCACACTGAGCGTGAGCCCTGGCGAGAGAGCCAGCATCAGCTGCAGGGCCTCCCAGAGCCTGGTGCACTCCAACGGCAATACCCACCTGCACTGGTATCAGCAGAGACCCGGCCAGGCCCCTAGGCTGCTGATCTACTCCGTGAGCAACAGGTTCTCCGAGGTGCCCGCCAGATTCAGCGGATCCGGCAGCGGCACCGACTTCACCCTCACCATCTCCAGCGTGGAGAGCGAGGACTTCGCCGTCTACTACTGCAGCCAGACAAGCCACATCCCCTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGGGCGGCGGCGGCAGCGGCGGCGGAGGCAGCGGAGGCGGCGGATCCCAGGTGCAACTGGTGCAGAGCGGAGCCGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGGTCAGCTGCAAGGCCAGCGGCAACACCCTGACAAACTACGTGATCCACTGGGTGAGGCAGGCCCCTGGCCAAAGGCTCGAGTGGATGGGCTACATCCTCCCCTACAACGACCTGACCAAGTACTCCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCAGCACCGCCTACATGGAACTCAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCACCAGGTGGGACTGGGATGGCTTCTTCGACCCTTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGC GCGCAGCTGCCTGCAGG 1376CTX-169 CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCGTGATGACACAATCCCCCCTCAGCCTGCCTGTGACACTGGGCCAGCCTGCCACCCTGAGCTGCAGGAGCACCCAGTCCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTTCCAGCAGAGGCCTGGACAGAGCCCCCTGAGGCTGATCTACAGCGTGAGCAACAGGGACTCCGGCGTGCCCGATAGATTCAGCGGCAGCGGCTCCGGCACCGATTTCACCCTGAAGATCTCCAGAGTGGAAGCCGAGGACGTGGGCGTCTACTACTGCAGCCAGACCAGCCATATCCCCTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGGGAGGCGGCGGAAGCGGCGGAGGCGGATCCGGAGGCGGAGGCTCCCAAGTGCAGCTGGTGCAGAGCGGCGCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGAAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAGGCCCCCGGACAGAGACTCGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGACAAGAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTGTACTACTGCACCAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGAACCACAGTGACCGTGTCCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGC GCGCAGCTGCCTGCAGG 1377CTX-170 CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTGCAGCTGCAGCAGAGCGGCCCTGAGCTGGTGAAGCCCGGCGCCAGCGTGAAGATCAGCTGCAAGACCTCCGGCTATACCTTTACCGAGTACACCATCAACTGGGTGAAGCAGAGCCACGGCAAGAGCCTGGAGTGGATCGGCGATATCTACCCCGACAACTACAACATCAGGTACAACCAGAAGTTCAAGGGCAAGGCCACCCTGACCGTGGACAAGTCCAGCAGCACCGCCTACATGGAGCTGAGGAGCCTGTCCAGCGAGGACTCCGCCATCTACTACTGCGCCAACCACGACTTTTTCGTCTTCTGGGGACAGGGCACCCTGGTGACAGTGTCCGCTGGCGGCGGCGGCAGCGGCGGCGGCGGCTCCGGAGGCGGCGGCAGCGACATCCAGATGACACAGGCCACAAGCTCCCTGTCCGCCAGCCTGGGCGATAGGGTGACCATCAATTGCAGGACCTCCCAGGACATCAGCAACCACCTGAACTGGTACCAGCAGAAACCCGACGGCACCGTGAAGCTGCTCATCTACTACACCAGCAGGCTGCAGTCCGGCGTCCCTAGCAGATTCAGCGGATCCGGCAGCGGCACCGACTATAGCCTGACCATCAGCAACCTCGAGCAGGAGGACATCGGCACCTACTTCTGCCATCAGGGCAACACCCTGCCCCCTACCTTTGGCGGCGGCACAAAGCTGGAGATTAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1378 CTX-171CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGATATCCAGATGACCCAGGCCACCAGCAGCCTGAGCGCTTCCCTCGGCGACAGGGTGACCATCAACTGCAGGACCAGCCAGGACATCTCCAACCACCTGAACTGGTACCAGCAGAAGCCCGACGGCACCGTGAAACTGCTGATCTACTACACCAGCAGACTGCAGAGCGGCGTGCCCTCCAGATTTTCCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATTAGCAACCTGGAGCAGGAGGACATCGGAACCTACTTCTGCCACCAGGGCAACACACTGCCTCCCACCTTCGGCGGCGGCACAAAGCTCGAGATCAAGGGCGGCGGCGGAAGCGGCGGCGGCGGCAGCGGCGGCGGAGGCTCCGAGGTGCAACTGCAACAGAGCGGACCTGAGCTGGTGAAGCCTGGCGCCAGCGTGAAGATCTCCTGTAAGACCAGCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGAGCCACGGCAAGAGCCTCGAATGGATCGGCGACATCTATCCCGACAACTACAATATCAGATACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGTGGATAAGTCCTCCTCCACCGCTTACATGGAGCTGAGGAGCCTGAGCAGCGAGGACTCCGCCATCTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAAGGCACCCTCGTGACCGTGAGCGCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1379 CTX-172CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGTCCGGCGCTGAGCTGAAGAAGCCCGGCGCCAGCGTGAAGATCAGCTGCAAGGCCAGCGGCTACACCTTCACCGAATACACCATCAACTGGGTGAGACAGGCCCCTGGACAGAGGCTCGAGTGGATGGGCGACATCTACCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGACACCAGCGCCAGCACCGCCTATATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTCTATTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACACTGGTGACCGTGTCCAGCGGCGGCGGCGGCAGCGGCGGCGGAGGAAGCGGCGGCGGCGGCAGCGATATCCAGATGACCCAGAGCCCCTCCTCCCTGAGCGCTAGCGTGGGCGACAGGGTGACCATTACCTGTCAGGCCTCCCAGGACATCAGCAACTACCTGAACTGGTACCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTATTACACCAGCAGGCTGGAGACCGGCGTGCCCTCCAGATTCAGCGGCTCCGGCTCCGGAACCGACTTCACCTTCACCATCAGCTCCCTGCAGCCTGAGGACATCGCCACCTACTACTGCCAGCAGGGCAACACCCTGCCTCCCACATTCGGCGGCGGCACAAAGGTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1380 CTX-173CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTCCAGTCCGGCGCCGAACTGAAGAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAGGCCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAGGCAAGCCCCCGGCCAGAGACTGGAGTGGATGGGCGACATCTACCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGATACCAGCGCCAGCACAGCCTATATGGAGCTGTCCTCCCTGAGATCCGAGGACACCGCCGTGTATTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAAGGCACCCTGGTGACCGTGAGCAGCGGCGGCGGCGGCTCCGGCGGCGGAGGCTCCGGAGGCGGAGGCAGCGACATCCAGATGACCCAGAGCCCTTCCAGCCTGAGCGCTAGCCTGGGCGACAGGGTGACCATCACCTGCAGGACCAGCCAGGACATCAGCAATCACCTGAACTGGTACCAGCAAAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCAGCAGGCTGGAAAGCGGCGTGCCTAGCAGGTTCAGCGGCAGCGGCTCCGGAACCGACTACAGCCTGACCATTAGCAGCCTGCAACCTGAGGACATCGGCACCTATTACTGCCAGCAGGGCAACACCCTGCCTCCTACCTTTGGCGGCGGCACCAAACTCGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1381 CTX-174CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGGCCCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGATCTCCTGCAAGACCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGGCCCCCGGACAGGGACTGGAATGGATCGGCGACATCTACCCCGACAACTACAACATCAGGTACAACCAGAAGTTCCAAGGCAAGGCCACCATCACAAGGGACACCAGCAGCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGATACCGCCGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCGGAGGAGGCGGAAGCGGAGGAGGAGGATCCGGAGGAGGAGGCAGCGACATCCAGATGACCCAGTCCCCCTCCTCCCTGAGCGCCTCCGTGGGAGACAGGGTGACCATCACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTGAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATTTACTACACCAGCAGGCTGGAAACCGGCGTGCCCAGCAGATTTAGCGGCAGCGGCAGCGGCACCGACTTTACCTTTACCATCTCCAGCCTGCAGCCCGAGGATATCGCCACATACTACTGCCAGCAGGGCAACACCCTCCCCCCTACCTTTGGCGGCGGCACCAAGGTGGAGATTAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1382 CTX-175CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGTCCGGCCCCGAACTGAAAAAGCCCGGCGCCAGCGTCAAGATCAGCTGCAAGACCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGGCCCCCGGCCAGGGACTGGAATGGATTGGCGACATCTACCCCGACAACTACAACATTAGGTATAACCAGAAGTTCCAGGGCAAGGCCACCATCACAAGAGACACCAGCAGCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACAGTGTCCAGCGGCGGCGGCGGCTCCGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGACATTCAGATGACACAGAGCCCCTCCAGCCTGAGCGCCAGCCTGGGCGATAGGGTGACCATCACCTGCAGAACCAGCCAGGACATCAGCAACCACCTGAATTGGTACCAGCAGAAGCCCGGAAAGGCCCCCAAACTGCTGATCTACTACACCAGCAGGCTGGAGAGCGGCGTGCCTAGCAGGTTTAGCGGCAGCGGCAGCGGCACAGATTACAGCCTGACCATCAGCAGCCTGCAGCCCGAAGACATCGGCACCTACTACTGCCAGCAGGGCAACACCCTGCCCCCTACCTTTGGCGGAGGCACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1383 CTX-176CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCCAGATGACACAGAGCCCTAGCAGCCTGAGCGCTTCCGTGGGCGACAGGGTGACCATCACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTCAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCTCCAGGCTGGAGACCGGAGTGCCCTCCAGATTTTCCGGCAGCGGCAGCGGCACCGATTTCACCTTCACCATCAGCAGCCTGCAGCCCGAGGACATCGCCACCTACTATTGCCAGCAGGGCAACACCCTGCCCCCCACATTTGGAGGCGGCACCAAGGTGGAGATCAAGGGCGGAGGAGGAAGCGGAGGAGGAGGAAGCGGAGGAGGCGGAAGCCAGGTGCAGCTGGTGCAGAGCGGCGCTGAGCTCAAGAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAAGCCTCCGGATACACCTTCACCGAGTACACCATCAATTGGGTGAGACAGGCCCCCGGCCAAAGACTGGAGTGGATGGGCGACATCTATCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGAGACACCAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAATCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACCGTCAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1384 CTX-177CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGATATCCAGATGACACAGAGCCCTAGCTCCCTGAGCGCCAGCCTGGGCGATAGGGTGACCATCACCTGCAGGACCTCCCAGGACATCAGCAACCACCTGAACTGGTACCAGCAGAAGCCCGGCAAAGCCCCCAAGCTGCTGATCTACTACACCAGCAGGCTGGAAAGCGGCGTGCCCAGCAGGTTTAGCGGAAGCGGCAGCGGCACCGACTACAGCCTGACCATCAGCTCCCTGCAGCCCGAGGACATCGGCACCTACTACTGCCAGCAGGGCAACACCCTGCCTCCCACCTTCGGAGGCGGAACCAAGCTGGAGATTAAGGGAGGCGGCGGAAGCGGCGGCGGCGGCTCCGGCGGAGGAGGCAGCCAGGTGCAGCTGGTGCAGTCCGGAGCCGAGCTGAAAAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAGGCCAGCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAGGCAGGCCCCTGGCCAGAGACTCGAGTGGATGGGCGACATCTACCCCGACAACTACTCCATCAGGTACAACCAGAAGTTTCAGGGCAGGGTGACCATTACCAGGGACACCAGCGCCAGCACAGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGATACAGCCGTCTACTACTGCGCCAACCACGACTTTTTCGTGTTCTGGGGACAGGGCACCCTGGTGACCGTGTCCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1385 CTX-178CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCCAAATGACCCAGAGCCCTAGCTCCCTGAGCGCTTCCGTGGGCGACAGAGTGACCATTACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTGAACTGGTATCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTACTACACCAGCAGGCTGGAGACCGGAGTGCCCAGCAGGTTTAGCGGCTCCGGATCCGGCACCGACTTCACCTTCACCATCTCCAGCCTGCAGCCCGAGGACATCGCCACCTACTACTGCCAGCAGGGCAATACCCTCCCCCCTACCTTCGGAGGCGGCACCAAGGTGGAGATCAAGGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGGCGGAGGCGGCAGCCAGGTGCAACTGGTGCAGAGCGGCCCTGAGCTGAAGAAACCCGGCGCCAGCGTGAAAATCAGCTGCAAGACCAGCGGCTACACATTCACCGAGTACACCATCAACTGGGTGAAGCAGGCTCCCGGACAGGGACTGGAGTGGATCGGCGACATCTACCCTGACAACTACAACATCAGATACAACCAAAAGTTCCAGGGCAAGGCCACCATCACCAGGGACACCAGCTCCTCCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACCGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1386 CTX-179CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGATATCCAGATGACACAAAGCCCCAGCAGCCTGTCCGCTAGCCTGGGCGATAGGGTGACCATCACATGCAGGACCAGCCAGGACATCTCCAACCACCTGAACTGGTACCAGCAGAAGCCTGGAAAGGCCCCCAAACTGCTGATCTACTACACCAGCAGGCTGGAGAGCGGCGTGCCTAGCAGGTTTTCCGGCAGCGGCAGCGGCACCGACTATAGCCTGACCATCAGCTCCCTGCAGCCCGAGGACATCGGCACCTACTACTGCCAGCAGGGAAACACACTGCCCCCCACCTTTGGCGGCGGCACAAAGCTGGAGATCAAGGGCGGCGGCGGATCCGGCGGCGGAGGCAGCGGAGGAGGAGGAAGCCAGGTGCAGCTGGTGCAGTCCGGCCCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAAATTAGCTGCAAGACCTCCGGCTACACATTCACCGAGTACACCATCAACTGGGTGAAGCAGGCTCCCGGCCAGGGACTGGAGTGGATCGGCGACATCTACCCCGACAACTACAACATCAGGTACAACCAGAAATTCCAGGGCAAGGCCACCATCACCAGGGACACCAGCTCCTCCACCGCCTATATGGAGCTGTCCAGCCTGAGAAGCGAGGATACCGCCGTGTACTACTGCGCCAACCACGATTTCTTCGTGTTCTGGGGCCAGGGCACACTGGTCACCGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1583 CTX-139.1CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTTGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATGGAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGGAAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGC CTGCAGG 1584 CTX-139.2CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTtgtttggtactttacagtttattaaatagatgtttatatggagaagctctcatttctttctcagaagagcctggctaggaaggtggatgaggcaccatattcattttgcaggtgaaattcctGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 1585 CTX-139.3CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTGCGGCCGCACGCGTTGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATGGAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGGAAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGACTATTCACCGATTTTGATTCTCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGTAACCACGTGCGGACCGAGGCTGCAGCGTCGTCCTCCCTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG

TABLE 35 Donor Template Nucleotide Sequences-Left Homology Arm toRight Homology Arm SEQ ID NO: Description Sequence 1387 LHA to RHA ofGAAGCCCAGAGCAGGGCCTTAGGGAAGCGGGACCCTGCTCTG CTX-131GGCGGAGGAATATGTCCCAGATAGCACTGGGGACTCTTTAAGGAAAGAAGGATGGAGAAAGAGAAAGGGAGTAGAGGCGGCCACGACCTGGTGAACACCTAGGACGCACCATTCTCACAAAGGGAGTTTTCCACACGGACACCCCCCTCCTCACCACAGCCCTGCCAGGACGGGGCTGGCTACTGGCCTTATCTCACAGGTAAAACTGACGCACGGAGGAACAATATAAATTGGGGACTAGAAAGGTGAAGAGCCAAAGTTAGAACTCAGGACCAACTTATTCTGATTTTGTTTTTCCAAACTGCTTCTCCTCTTGGGAAGTGTAAGGAAGCTGCAGCACCAGGATCAGTGAAACGCACCAGACGGCCGCGTCAGAGCAGCTCAGGTTCTGGGAGAGGGTAGCGCAGGGTGGCCACTGAGAACCGGGCAGGTCACGCATCCCCCCCTTCCCTCCCACCCCCTGCCAAGCTCTCCCTCCCAGGATCCTCTCTGGCTCCATCGTAAGCAAACCTTAGAGGTTCTGGCAAGGAGAGAGATGGCTCCAGGAAATGGGGGTGTGTCACCAGATAAGGAATCTGCCTAACAGGAGGTGGGGGTTAGACCCAATATCAGGAGACTAGGAAGGAGGAGGCCTAAGGATGGGGCTTTTCTGTCACCAGCCACTAGTGGCCGCCAGTGTGATGGATATCTGCAGAATTCGCCCTTATGGGGATCCGAACAGAGAGACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGTTGGAACAGCAGAATATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGGGCCAAGAACAGATGGTCCCCAGATGCGGTCCCGCCCTCAGCAGTTTCTAGAGAACCATCAGATGTTTCCAGGGTGCCCCAAGGACCTGAAATGACCCTGTGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCGCGCTTCTGCTCCCCGAGCTCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACCGACTCTAGAGGGACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGACTGTGGGGTGGAGGGGACAGATAAAAGTACCCAGAACCAGAGCCACATTAACCGGCCCTGGGAATATAAGGTGGTCCCAGCTCGGGGACACAGGATCCCTGGAGGCAGCAAACATGCTGTCCTGAAGTGGACATAGGGGCCCGGGTTGGAGGAAGAAGACTAGCTGAGCTCTCGGACCCCTGGAAGATGCCATGACAGGGGGCTGGAAGAGCTAGCACAGACTAGAGAGGTAAGGGGGGTAGGGGAGCTGCCCAAATGAAAGGAGTGAGAGGTGACCCGAATCCACAGGAGAACGGGGTGTCCAGGCAAAGAAAGCAAGAGGATGGAGAGGTGGCTAAAGCCAGGGAGACGGGGTACTTTGGGGTTGTCCAGAAAAACGGTGATGATGCAGGCCTACAAGAAGGGGAGGCGGGACGCAAGGGAGACATCCGTCGGAGAAGGCCATCCTAAGAAACGAGAGATGGCACAGGCCCCAGAAGGAGAAGGAAAAGGGAACCCAGCGAGTGAAGACGGCATGGGGTTGGGTGAGGGAGGAGAGATGCCCGGAGAGGACCCAGACACGGGGAGGATCCGCTCAGAGGACATCACGTGGTGCAGCGCCGAGAAGGAAGTGCTCCGGAAAGAGCATCCTTGGGCAGCAACACAGCAGAGAGCAAGGGGAAGAGGGAGTGGAGGAAG ACGGAACCTGAAGGAGGCGGC 1388LHA to RHA of GAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAG CTX-133CCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCC 1389 LHA to RHA ofTTTTGTAAAGAATATAGGTAAAAAGTGGCATTTTTTCTTTGGAT CTX-135TTAATTCTTATGGATTTAAGTCAACATGTATTTTCAAGCCAACAAGTTTTGTTAATAAGATGGCTGCACCCTGCTGCTCCATGCCAGATCCACCACACAGAAAGCAAATGTTCAGTGCATCTCCCTCTTCCTGTCAGAGCTTATAGAGGAAGGAAGACCCCGCAATGTGGAGGCATATTGTATTACAATTACTTTTAATGGCAAAAACTGCAGTTACTTTTGTGCCAACCTACTACATGGTCTGGACAGCTAAATGTCATGTATTTTTCATGGCCCCTCCAGGTATTGTCAGAGTCCTCTTGTTTGGCCTTCTAGGAAGGCTGTGGGACCCAGCTTTCTTCAACCAGTCCAGGTGGAGGCCTCTGCCTTGAACGTTTCCAAGTGAGGTAAAACCCGCAGGCCCAGAGGCCTCTCTACTTCCTGTGTGGGGTTCAGAAACCCTCCTCCCCTCCCAGCCTCAGGTGCCTGCTTCAGAAAATGGTGAGTCTCTCTCTTATAAAGCCCTCCTTTTTCATCCTAGCATTGGGAACAATGGCCCCAGGGTCCTTATCTCTAGCAGATGTTTTGAAAAAGTCATCTGTTTTGCTTTTTTTCCAGAAGTAGTAAGTCTGCTGGCCTCCGCCATCTTAGTAAAGTAACAGTCCCATGAAACAAAGATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGGTGAGTAGGATGGAGTGGAAAGGGTGGTGTGTCTCCAGACCGCTGGAAGGCTTACAGCCTTACCTGGCACTGCCTAGTGGCACCAAGGAGCCTCATTTACCAGATGTAAGGAACTGTTTGTGCTATGTTAGGGTGAGGGATTAGAGCTGGGGACTAAAGAAAAAGATAGGCCACGGGTGCCTGGGAGAGCGTTCGGGGAGCAGGCAAAGAAGAGCAGTTGGGGTGATCATAGCTATTGTGAGCAGAGAGGTCTCGCTACCTCTAAGTACGAGCTCATTCCAACTTACCCAGCCCTCCAGAACTAACCCAAAAGAGACTGGAAGAGCGAAGCTCCACTCCTTGTTTTGAAGAGACCAGATACTTGCGTCCAAACTCTGCACAGGGCATATATAGCAATTCACTATCTTTGAGACCATAAAACGCCTCGTAATTTTTAGTCCTTTTCAAGTGACCAACAACTTTCAGTTTATTTCATTTTTTTGAAGCAAGATGGATTATGAATTGATAAATAACCAAGAGCATTTCTGTATCTCATATGAGATAAATAATACCAAAAAAAGTTGCCATTTATTGTCAGATACTGTGTAAAGAAAAAATTATTTAGACGTGTTAACTGGTTTAATCCTACTTCTGCCTAGGAAGGAAGGTGTTATATCCTCTTTTTAAAATTCTTTTTAATTTTGACTATATAAACTGATAA 1390 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-138AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCT GGGACAGGAGCTCAATGAGAAAGG1391 LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-139AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1392 LHA to RHA ofTAATCCTCCGGCAAACCTCTGTTTCCTCCTCAAAAGGCAGGAG CTX-140GTCGGAAAGAATAAACAATGAGAGTCACATTAAAAACACAAAATCCTACGGAAATACTGAAGAATGAGTCTCAGCACTAAGGAAAAGCCTCCAGCAGCTCCTGCTTTCTGAGGGTGAAGGATAGACGCTGTGGCTCTGCATGACTCACTAGCACTCTATCACGGCCATATTCTGGCAGGGTCAGTGGCTCCAACTAACATTTGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATGGAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGGAAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGAGAAGAGCAGCAGGCATGAGTTGAATGAAGGAGGCAGGGCCGGGTCACAG GG 1393 LHA to RHA ofTAATCCTCCGGCAAACCTCTGTTTCCTCCTCAAAAGGCAGGAG CTX-141GTCGGAAAGAATAAACAATGAGAGTCACATTAAAAACACAAAATCCTACGGAAATACTGAAGAATGAGTCTCAGCACTAAGGAAAAGCCTCCAGCAGCTCCTGCTTTCTGAGGGTGAAGGATAGACGCTGTGGCTCTGCATGACTCACTAGCACTCTATCACGGCCATATTCTGGCAGGGTCAGTGGCTCCAACTAACATTTGTTTGGTACTTTACAGTTTATTAAATAGATGTTTATATGGAGAAGCTCTCATTTCTTTCTCAGAAGAGCCTGGCTAGGAAGGTGGATGAGGCACCATATTCATTTTGCAGGTGAAATTCCTGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCGAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCCATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCATCCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGGAGAAGAGCAGCAGGCATGAGTTGAATGAAGGAGGCAGGGC CGGGTCACAGGG 1394LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-142AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGATATAGTTATGACCCAATCACCCGATAGTCTTGCGGTAAGCCTGGGGGAGCGAGCAACAATAAACTGTCGGGCATCAAAATCCGTCAGTACAAGCGGGTATTCATTCATGCACTGGTATCAACAGAAACCCGGTCAGCCACCCAAGCTCCTGATTTATCTTGCGTCTAATCTTGAGTCCGGCGTCCCAGACCGGTTTTCCGGCTCCGGGAGCGGCACGGATTTTACTCTTACTATTTCTAGCCTTCAGGCCGAAGATGTGGCGGTATACTACTGCCAGCATTCAAGGGAAGTTCCTTGGACGTTCGGTCAGGGCACGAAAGTGGAAATTAAAGGCGGGGGGGGATCCGGCGGGGGAGGGTCTGGAGGAGGTGGCAGTGGTCAGGTCCAACTGGTGCAGTCCGGGGCAGAGGTAAAAAAACCCGGCGCGTCTGTTAAGGTTTCATGCAAGGCCAGTGGATATACTTTCACCAATTACGGAATGAACTGGGTGAGGCAGGCCCCTGGTCAAGGCCTGAAATGGATGGGATGGATAAACACGTACACCGGTGAACCTACCTATGCCGATGCCTTTAAGGGTCGGGTTACGATGACGAGAGACACCTCCATATCAACAGCCTACATGGAGCTCAGCAGATTGAGGAGTGACGATACGGCAGTCTATTACTGTGCAAGAGACTACGGCGATTATGGCATGGATTACTGGGGCCAGGGCACTACAGTAACCGTTTCCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGA GGCCTGGGACAGGAGCTCAATGAGAAAGG1395 LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-145AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTCCAGTTGGTGCAAAGCGGGGCGGAGGTGAAAAAACCCGGCGCTTCCGTGAAGGTGTCCTGTAAGGCGTCCGGTTATACGTTCACGAACTACGGGATGAATTGGGTTCGCCAAGCGCCGGGGCAGGGACTGAAATGGATGGGGTGGATAAATACCTACACCGGCGAACCTACATACGCCGACGCTTTTAAAGGGCGAGTCACTATGACGCGCGATACCAGCATATCCACCGCATACATGGAGCTGTCCCGACTCCGGTCAGACGACACGGCTGTCTACTATTGTGCTCGGGACTATGGCGATTATGGCATGGACTACTGGGGTCAGGGTACGACTGTAACAGTTAGTAGTGGTGGAGGCGGCAGTGGCGGGGGGGGAAGCGGAGGAGGGGGTTCTGGTGACATAGTTATGACCCAATCCCCAGATAGTTTGGCGGTTTCTCTGGGCGAGAGGGCAACGATTAATTGTCGCGCATCAAAGAGCGTTTCAACGAGCGGATATTCTTTTATGCATTGGTACCAGCAAAAACCCGGACAACCGCCGAAGCTGCTGATCTACTTGGCTTCAAATCTTGAGTCTGGGGTGCCGGACCGATTTTCTGGTAGTGGAAGCGGAACTGACTTTACGCTCACGATCAGTTCACTGCAGGCTGAGGATGTAGCGGTCTATTATTGCCAGCACAGTAGAGAAGTCCCCTGGACCTTCGGTCAAGGCACGAAAGTAGAAATTAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1396 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-145bAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTCCAGTTGGTGCAAAGCGGGGCGGAGGTGAAAAAACCCGGCGCTTCCGTGAAGGTGTCCTGTAAGGCGTCCGGTTATACGTTCACGAACTACGGGATGAATTGGGTTCGCCAAGCGCCGGGGCAGGGACTGAAATGGATGGGGTGGATAAATACCTACACCGGCGAACCTACATACGCCGACGCTTTTAAAGGGCGAGTCACTATGACGCGCGATACCAGCATATCCACCGCATACATGGAGCTGTCCCGACTCCGGTCAGACGACACGGCTGTCTACTATTGTGCTCGGGACTATGGCGATTATGGCATGGACTACTGGGGTCAGGGTACGACTGTAACAGTTAGTAGTGGTGGAGGCGGCAGTGGCGGGGGGGGAAGCGGAGGAGGGGGTTCTGGTGACATAGTTATGACCCAATCCCCAGATAGTTTGGCGGTTTCTCTGGGCGAGAGGGCAACGATTAATTGTCGCGCATCAAAGAGCGTTTCAACGAGCGGATATTCTTTTATGCATTGGTACCAGCAAAAACCCGGACAACCGCCGAAGCTGCTGATCTACTTGGCTTCAAATCTTGAGTCTGGGGTGCCGGACCGATTTTCTGGTAGTGGAAGCGGAACTGACTTTACGCTCACGATCAGTTCACTGCAGGCTGAGGATGTAGCGGTCTATTATTGCCAGCACAGTAGAGAAGTCCCCTGGACCTTCGGTCAAGGCACGAAAGTAGAAATTAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1397 LHA to RHA ofGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAG CTX-152CCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTGCTTCATGCTGCTAGACCTCAGGTGCAGTTACAACAGTCAGGAGGAGGATTAGTGCAGCCAGGAGGATCTCTGAAACTGTCTTGTGCCGCCAGCGGAATCGATTTTAGCAGGTACTGGATGTCTTGGGTGAGAAGAGCCCCTGGAAAAGGACTGGAGTGGATCGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGTCTTCTGGAGGAGGAGGATCCGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGAGATATTGTGATGACACAAAGCCAGCGGTTCATGACCACATCTGTGGGCGACAGAGTGAGCGTGACCTGTAAAGCTTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCCAGACAGAGCCCTAAAGCCCTGATCTTTTCTGCCAGCCTGAGATTTTCTGGCGTTCCTGCCAGATTTACCGGCTCTGGCTCTGGCACCGATTTTACACTGACCATCAGCAATCTGCAGTCTGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAACTACCCCCTGACCTTTGGAGCTGGCACAAAACTGGAGCTGAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCC 1398 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-153AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTGCTTCATGCTGCTAGACCTCAGGTGCAGTTACAACAGTCAGGAGGAGGATTAGTGCAGCCAGGAGGATCTCTGAAACTGTCTTGTGCCGCCAGCGGAATCGATTTTAGCAGGTACTGGATGTCTTGGGTGAGAAGAGCCCCTGGAAAAGGACTGGAGTGGATCGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGTCTTCTGGAGGAGGAGGATCCGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGAGATATTGTGATGACACAAAGCCAGCGGTTCATGACCACATCTGTGGGCGACAGAGTGAGCGTGACCTGTAAAGCTTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCCAGACAGAGCCCTAAAGCCCTGATCTTTTCTGCCAGCCTGAGATTTTCTGGCGTTCCTGCCAGATTTACCGGCTCTGGCTCTGGCACCGATTTTACACTGACCATCAGCAATCTGCAGTCTGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAACTACCCCCTGACCTTTGGAGCTGGCACAAAACTGGAGCTGAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGG ACAGGAGCTCAATGAGAAA 1399LHA to RHA of GAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAG CTX-154CCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTGCTTCATGCTGCTAGACCTGACATCGTGATGACCCAAAGCCAGAGGTTCATGACCACATCTGTGGGCGATAGAGTGAGCGTGACCTGTAAAGCCTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCTAGACAGAGCCCTAAAGCCCTGATCTTTAGCGCCAGCCTGAGATTTAGCGGAGTTCCTGCCAGATTTACCGGAAGCGGATCTGGAACCGATTTTACACTGACCATCAGCAACCTGCAGAGCGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAATTACCCTCTGACCTTTGGAGCCGGCACAAAGCTGGAGCTGAAAGGAGGAGGAGGATCTGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGACAAGTTCAATTACAGCAATCTGGAGGAGGACTGGTTCAGCCTGGAGGAAGCCTGAAGCTGTCTTGTGCCGCTTCTGGAATCGATTTTAGCAGATACTGGATGAGCTGGGTGAGAAGAGCCCCTGGCAAAGGACTGGAGTGGATTGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGAGGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGAGGAGAACCCTGGACCTATGGTGAGCAAGGGCGAGGAGCTGTTCACCGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGCTGTACAAGTAATAATAAAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCC 1400 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-155AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTGCTTCATGCTGCTAGACCTGACATCGTGATGACCCAAAGCCAGAGGTTCATGACCACATCTGTGGGCGATAGAGTGAGCGTGACCTGTAAAGCCTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCTAGACAGAGCCCTAAAGCCCTGATCTTTAGCGCCAGCCTGAGATTTAGCGGAGTTCCTGCCAGATTTACCGGAAGCGGATCTGGAACCGATTTTACACTGACCATCAGCAACCTGCAGAGCGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAATTACCCTCTGACCTTTGGAGCCGGCACAAAGCTGGAGCTGAAAGGAGGAGGAGGATCTGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGACAAGTTCAATTACAGCAATCTGGAGGAGGACTGGTTCAGCCTGGAGGAAGCCTGAAGCTGTCTTGTGCCGCTTCTGGAATCGATTTTAGCAGATACTGGATGAGCTGGGTGAGAAGAGCCCCTGGCAAAGGACTGGAGTGGATTGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCT GGGACAGGAGCTCAATGAGAAA 1401LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-160AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTCCAGCTGGTGGAGAGCGGCGGAGGACTGGTCCAGCCTGGCGGCTCCCTGAAACTGAGCTGCGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAATGGATCGGCGAGATCAACCCCGACTCCAGCACCATCAACTACGCCGACAGCGTCAAGGGCAGGTTCACCATTAGCAGGGACAATGCCAAGAACACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAAGACACCGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCTCCGGAGGAGGCGGCAGCGGCGGAGGCGGCAGCGGCGGAGGCGGCAGCGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCTCCGTGGGAGATAGGGTGACAATCACCTGTAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTATCAACAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTTTCCGCCTCCCTGAGGTTCAGCGGAGTCCCCAGCAGGTTCTCCGGATCCGGCTCCGGAACCGACTTTACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAGCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCT GGGACAGGAGCTCAATGAGAAAGG 1402LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-160bAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTCCAGCTGGTGGAGAGCGGCGGAGGACTGGTCCAGCCTGGCGGCTCCCTGAAACTGAGCTGCGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAATGGATCGGCGAGATCAACCCCGACTCCAGCACCATCAACTACGCCGACAGCGTCAAGGGCAGGTTCACCATTAGCAGGGACAATGCCAAGAACACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAAGACACCGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCTCCGGAGGAGGCGGCAGCGGCGGAGGCGGCAGCGGCGGAGGCGGCAGCGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCTCCGTGGGAGATAGGGTGACAATCACCTGTAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTATCAACAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTTTCCGCCTCCCTGAGGTTCAGCGGAGTCCCCAGCAGGTTCTCCGGATCCGGCTCCGGAACCGACTTTACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAGCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGG CCTGGGACAGGAGCTCAATGAGAAAGG1403 LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-161AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCAGCCCGGAGGCTCCCTGAAGCTGAGCTGCGCTGCCTCCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGGCAGGCTCCCGGCAAAGGCCTGGAGTGGATCGGCGAGATCAACCCCGACAGCAGCACCATCAACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAATACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAGGACACAGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGAGACGCTATGGACTACTGGGGCCAGGGAACCCTGGTGACCGTGAGCAGCGGAGGCGGAGGCTCCGGCGGCGGAGGCAGCGGAGGAGGCGGCAGCGATATCCAGATGACCCAGTCCCCCAGCTCCCTGAGCGCTAGCCCTGGCGACAGGGTGAGCGTGACATGCAAGGCCAGCCAGAGCGTGGACAGCAACGTGGCCTGGTACCAGCAGAAACCCAGACAGGCCCCCAAGGCCCTGATCTTCAGCGCCAGCCTGAGGTTTAGCGGCGTGCCCGCTAGGTTTACCGGATCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCAACCTGCAGTCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAACTACCCCCTGACATTCGGCGCCGGAACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCT GGGACAGGAGCTCAATGAGAAAGG1404 LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-162AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCTAGCGTGGGCGACAGGGTGACCATCACCTGCAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTACCAGCAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTCAGCGCCAGCCTGAGGTTCTCCGGAGTGCCTAGCAGATTTAGCGGCAGCGGCAGCGGCACAGACTTCACCCTGACCATCAGCAGCCTCCAGCCCGAGGATTTCGCCACCTACTACTGCCAGCAGTACAACTCCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGGGAGGAGGAGGAAGCGGAGGAGGAGGAAGCGGAGGCGGAGGAAGCGAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGCAACCTGGAGGCAGCCTGAAGCTGAGCTGTGCCGCCAGCGGAATCGACTTCAGCAGGTACTGGATGTCCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAGTGGATCGGAGAGATCAACCCCGACAGCTCCACCATCAACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGAGACAACGCCAAGAACACCCTGTACCTGCAGATGAACCTGTCCAGAGCCGAGGACACCGCCCTGTACTACTGCGCCAGCCTGTATTACGACTACGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCT GGGACAGGAGCTCAATGAGAAAGG 1405LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-163AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCCAAATGACCCAGTCCCCTAGCAGCCTGTCCGCCAGCCCTGGAGACAGGGTGTCCGTGACCTGCAAGGCCAGCCAGTCCGTGGACAGCAACGTCGCCTGGTATCAGCAGAAGCCCAGGCAAGCTCCCAAGGCTCTGATCTTCTCCGCCAGCCTGAGATTTTCCGGCGTGCCCGCCAGATTCACCGGAAGCGGCAGCGGCACCGACTTCACCCTGACCATCAGCAACCTGCAGAGCGAGGATTTCGCCACATACTACTGCCAGCAGTACAACAACTACCCCCTGACCTTCGGAGCCGGCACCAAGCTGGAGATCAAAGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGATCCGAAGTGCAGCTGGTGGAAAGCGGAGGCGGACTCGTGCAGCCTGGCGGAAGCCTGAAGCTGAGCTGTGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGGCAGGCTCCCGGCAAAGGCCTGGAGTGGATCGGCGAGATCAACCCTGACAGCAGCACCATCAACTACGCCGACAGCGTGAAAGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACACCCTGTACCTGCAGATGAACCTGTCCAGAGCCGAGGACACCGCCCTGTACTACTGCGCCAGCCTGTACTACGACTACGGCGACGCTATGGACTACTGGGGCCAAGGCACCCTCGTGACCGTCAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCT GGGACAGGAGCTCAATGAGAAAGG 1406LHA to RHA of GAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-164AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTGCAGCTGCAGCAGTCCGGCCCTGAGCTCGTGAAGCCTGGAGCCAGCGTGAAAATGAGCTGTAAGGCCTCCGGCAACACCCTCACCAACTACGTGATCCATTGGATGAAGCAGATGCCCGGCCAGGGCCTGGACTGGATTGGCTACATTCTGCCCTACAACGACCTGACCAAGTACAACGAGAAGTTCACCGGCAAGGCCACCCTGACCAGCGATAAGAGCTCCAGCAGCGCCTACATGGAGCTGAACTCCCTGACCAGCGAGGACAGCGCCGTGTACTACTGCACCAGGTGGGACTGGGATGGCTTCTTCGACCCCTGGGGACAGGGCACCACCCTGACAGTGTCCAGCGGAGGAGGCGGCAGCGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGATATCGTGATGACACAGTCCCCTCTGAGCCTGCCTGTGAGCCTGGGCGACCAGGCCAGCATCAGCTGCAGGTCCACCCAGTCCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTACCTGCAAAGGCCCGGCCAGTCCCCTAAGCTGCTGATCTACAGCGTGAGCAACAGGTTTAGCGAGGTGCCCGATAGATTTTCCGCCAGCGGCAGCGGCACCGACTTCACACTGAAGATCTCCAGGGTGGAGGCCGAGGATCTGGGCGTGTACTTCTGCAGCCAGACCAGCCACATCCCCTACACCTTCGGCGGCGGAACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1407 LHA to RHAGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-165AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCGTGATGACCCAGAGCCCCCTGAGCCTGCCTGTGTCCCTGGGAGACCAGGCTTCCATCAGCTGCAGGTCCACCCAGAGCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTACCTGCAGAGGCCTGGCCAGTCCCCCAAGCTGCTGATCTACAGCGTGAGCAATAGGTTCAGCGAGGTGCCCGACAGATTCAGCGCCAGCGGAAGCGGCACCGACTTCACCCTGAAGATCAGCAGGGTCGAGGCCGAAGATCTGGGCGTGTACTTCTGCTCCCAGACATCCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATTAAGGGCGGCGGAGGATCCGGCGGAGGAGGATCCGGAGGAGGAGGAAGCGAGGTGCAGCTGCAGCAGAGCGGACCCGAGCTGGTGAAACCCGGAGCCAGCGTCAAAATGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTCATCCACTGGATGAAGCAGATGCCCGGACAGGGCCTGGACTGGATCGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAACGAGAAATTCACCGGCAAGGCCACCCTGACCAGCGACAAGAGCAGCAGCAGCGCCTACATGGAGCTGAACAGCCTGACCAGCGAGGACTCCGCCGTGTACTATTGCACCAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACACTCACCGTGAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1408 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-166AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGGAGCCGAGCTCAAGAAGCCCGGAGCCTCCGTGAAGGTGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAAGCCCCCGGCCAAAGGCTGGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCTCCACCGCCTATATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGTACAAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACAGTGACCGTCAGCAGCGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGAAGCGAAATCGTGATGACCCAGAGCCCCGCCACACTGAGCGTGAGCCCTGGCGAGAGGGCCAGCATCTCCTGCAGGGCTAGCCAAAGCCTGGTGCACAGCAACGGCAACACCCACCTGCACTGGTACCAGCAGAGACCCGGACAGGCTCCCAGGCTGCTGATCTACAGCGTGAGCAACAGGTTCTCCGAGGTGCCTGCCAGGTTTAGCGGCAGCGGAAGCGGCACCGACTTTACCCTGACCATCAGCAGCGTGGAGTCCGAGGACTTCGCCGTGTATTACTGCAGCCAGACCAGCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1409 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-166bAGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGGAGCCGAGCTCAAGAAGCCCGGAGCCTCCGTGAAGGTGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAAGCCCCCGGCCAAAGGCTGGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCTCCACCGCCTATATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGTACAAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACAGTGACCGTCAGCAGCGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGAAGCGAAATCGTGATGACCCAGAGCCCCGCCACACTGAGCGTGAGCCCTGGCGAGAGGGCCAGCATCTCCTGCAGGGCTAGCCAAAGCCTGGTGCACAGCAACGGCAACACCCACCTGCACTGGTACCAGCAGAGACCCGGACAGGCTCCCAGGCTGCTGATCTACAGCGTGAGCAACAGGTTCTCCGAGGTGCCTGCCAGGTTTAGCGGCAGCGGAAGCGGCACCGACTTTACCCTGACCATCAGCAGCGTGGAGTCCGAGGACTTCGCCGTGTATTACTGCAGCCAGACCAGCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAA GG 1410 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-167AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGGCGCCGAGCTGAAGAAACCTGGCGCCAGCGTCAAGGTGAGCTGCAAGGCTTCCGGAAACACCCTCACCAACTACGTGATCCACTGGGTGAGGCAGGCCCCCGGACAGAGACTGGAGTGGATGGGCTACATTCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTCACCATCACCAGGGACAAGAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGTCCGAGGACACAGCCGTGTACTACTGCACCAGGTGGGACTGGGACGGATTCTTCGACCCTTGGGGCCAAGGCACCACAGTGACAGTGAGCTCCGGCGGAGGCGGCAGCGGCGGCGGAGGAAGCGGCGGCGGCGGAAGCGACATCGTGATGACCCAGAGCCCTCTGAGCCTGCCCGTGACACTGGGACAGCCTGCCACACTGTCCTGCAGGAGCACCCAGAGCCTGGTGCATAGCAACGGCAACACCCACCTGCACTGGTTCCAGCAGAGACCTGGCCAGAGCCCCCTGAGACTGATCTACAGCGTGAGCAACAGGGACAGCGGCGTGCCCGATAGATTTAGCGGCAGCGGCAGCGGCACCGACTTTACCCTGAAAATCTCCAGGGTGGAGGCCGAGGATGTGGGCGTGTATTACTGCTCCCAGACAAGCCACATTCCCTATACATTCGGCGGCGGCACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1411 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-168AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAAATCGTGATGACCCAGAGCCCTGCCACACTGAGCGTGAGCCCTGGCGAGAGAGCCAGCATCAGCTGCAGGGCCTCCCAGAGCCTGGTGCACTCCAACGGCAATACCCACCTGCACTGGTATCAGCAGAGACCCGGCCAGGCCCCTAGGCTGCTGATCTACTCCGTGAGCAACAGGTTCTCCGAGGTGCCCGCCAGATTCAGCGGATCCGGCAGCGGCACCGACTTCACCCTCACCATCTCCAGCGTGGAGAGCGAGGACTTCGCCGTCTACTACTGCAGCCAGACAAGCCACATCCCCTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGGGCGGCGGCGGCAGCGGCGGCGGAGGCAGCGGAGGCGGCGGATCCCAGGTGCAACTGGTGCAGAGCGGAGCCGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGGTCAGCTGCAAGGCCAGCGGCAACACCCTGACAAACTACGTGATCCACTGGGTGAGGCAGGCCCCTGGCCAAAGGCTCGAGTGGATGGGCTACATCCTCCCCTACAACGACCTGACCAAGTACTCCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCAGCACCGCCTACATGGAACTCAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCACCAGGTGGGACTGGGATGGCTTCTTCGACCCTTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1412 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-169AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCGTGATGACACAATCCCCCCTCAGCCTGCCTGTGACACTGGGCCAGCCTGCCACCCTGAGCTGCAGGAGCACCCAGTCCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTTCCAGCAGAGGCCTGGACAGAGCCCCCTGAGGCTGATCTACAGCGTGAGCAACAGGGACTCCGGCGTGCCCGATAGATTCAGCGGCAGCGGCTCCGGCACCGATTTCACCCTGAAGATCTCCAGAGTGGAAGCCGAGGACGTGGGCGTCTACTACTGCAGCCAGACCAGCCATATCCCCTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGGGAGGCGGCGGAAGCGGCGGAGGCGGATCCGGAGGCGGAGGCTCCCAAGTGCAGCTGGTGCAGAGCGGCGCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGAAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAGGCCCCCGGACAGAGACTCGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGACAAGAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTGTACTACTGCACCAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGAACCACAGTGACCGTGTCCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATGAGAAAGG 1413 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-170AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGAGGTGCAGCTGCAGCAGAGCGGCCCTGAGCTGGTGAAGCCCGGCGCCAGCGTGAAGATCAGCTGCAAGACCTCCGGCTATACCTTTACCGAGTACACCATCAACTGGGTGAAGCAGAGCCACGGCAAGAGCCTGGAGTGGATCGGCGATATCTACCCCGACAACTACAACATCAGGTACAACCAGAAGTTCAAGGGCAAGGCCACCCTGACCGTGGACAAGTCCAGCAGCACCGCCTACATGGAGCTGAGGAGCCTGTCCAGCGAGGACTCCGCCATCTACTACTGCGCCAACCACGACTTTTTCGTCTTCTGGGGACAGGGCACCCTGGTGACAGTGTCCGCTGGCGGCGGCGGCAGCGGCGGCGGCGGCTCCGGAGGCGGCGGCAGCGACATCCAGATGACACAGGCCACAAGCTCCCTGTCCGCCAGCCTGGGCGATAGGGTGACCATCAATTGCAGGACCTCCCAGGACATCAGCAACCACCTGAACTGGTACCAGCAGAAACCCGACGGCACCGTGAAGCTGCTCATCTACTACACCAGCAGGCTGCAGTCCGGCGTCCCTAGCAGATTCAGCGGATCCGGCAGCGGCACCGACTATAGCCTGACCATCAGCAACCTCGAGCAGGAGGACATCGGCACCTACTTCTGCCATCAGGGCAACACCCTGCCCCCTACCTTTGGCGGCGGCACAAAGCTGGAGATTAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAAT GAGAAAGG 1414 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-171AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGATATCCAGATGACCCAGGCCACCAGCAGCCTGAGCGCTTCCCTCGGCGACAGGGTGACCATCAACTGCAGGACCAGCCAGGACATCTCCAACCACCTGAACTGGTACCAGCAGAAGCCCGACGGCACCGTGAAACTGCTGATCTACTACACCAGCAGACTGCAGAGCGGCGTGCCCTCCAGATTTTCCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATTAGCAACCTGGAGCAGGAGGACATCGGAACCTACTTCTGCCACCAGGGCAACACACTGCCTCCCACCTTCGGCGGCGGCACAAAGCTCGAGATCAAGGGCGGCGGCGGAAGCGGCGGCGGCGGCAGCGGCGGCGGAGGCTCCGAGGTGCAACTGCAACAGAGCGGACCTGAGCTGGTGAAGCCTGGCGCCAGCGTGAAGATCTCCTGTAAGACCAGCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGAGCCACGGCAAGAGCCTCGAATGGATCGGCGACATCTATCCCGACAACTACAATATCAGATACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGTGGATAAGTCCTCCTCCACCGCTTACATGGAGCTGAGGAGCCTGAGCAGCGAGGACTCCGCCATCTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAAGGCACCCTCGTGACCGTGAGCGCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAAT GAGAAAGG 1415 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-172AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGTCCGGCGCTGAGCTGAAGAAGCCCGGCGCCAGCGTGAAGATCAGCTGCAAGGCCAGCGGCTACACCTTCACCGAATACACCATCAACTGGGTGAGACAGGCCCCTGGACAGAGGCTCGAGTGGATGGGCGACATCTACCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGACACCAGCGCCAGCACCGCCTATATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTCTATTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACACTGGTGACCGTGTCCAGCGGCGGCGGCGGCAGCGGCGGCGGAGGAAGCGGCGGCGGCGGCAGCGATATCCAGATGACCCAGAGCCCCTCCTCCCTGAGCGCTAGCGTGGGCGACAGGGTGACCATTACCTGTCAGGCCTCCCAGGACATCAGCAACTACCTGAACTGGTACCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTATTACACCAGCAGGCTGGAGACCGGCGTGCCCTCCAGATTCAGCGGCTCCGGCTCCGGAACCGACTTCACCTTCACCATCAGCTCCCTGCAGCCTGAGGACATCGCCACCTACTACTGCCAGCAGGGCAACACCCTGCCTCCCACATTCGGCGGCGGCACAAAGGTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATG AGAAAGG 1416 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-173AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTCCAGTCCGGCGCCGAACTGAAGAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAGGCCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAGGCAAGCCCCCGGCCAGAGACTGGAGTGGATGGGCGACATCTACCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGATACCAGCGCCAGCACAGCCTATATGGAGCTGTCCTCCCTGAGATCCGAGGACACCGCCGTGTATTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAAGGCACCCTGGTGACCGTGAGCAGCGGCGGCGGCGGCTCCGGCGGCGGAGGCTCCGGAGGCGGAGGCAGCGACATCCAGATGACCCAGAGCCCTTCCAGCCTGAGCGCTAGCCTGGGCGACAGGGTGACCATCACCTGCAGGACCAGCCAGGACATCAGCAATCACCTGAACTGGTACCAGCAAAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCAGCAGGCTGGAAAGCGGCGTGCCTAGCAGGTTCAGCGGCAGCGGCTCCGGAACCGACTACAGCCTGACCATTAGCAGCCTGCAACCTGAGGACATCGGCACCTATTACTGCCAGCAGGGCAACACCCTGCCTCCTACCTTTGGCGGCGGCACCAAACTCGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAATG AGAAAGG 1417 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-174AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGGCCCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGATCTCCTGCAAGACCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGGCCCCCGGACAGGGACTGGAATGGATCGGCGACATCTACCCCGACAACTACAACATCAGGTACAACCAGAAGTTCCAAGGCAAGGCCACCATCACAAGGGACACCAGCAGCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGATACCGCCGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCGGAGGAGGCGGAAGCGGAGGAGGAGGATCCGGAGGAGGAGGCAGCGACATCCAGATGACCCAGTCCCCCTCCTCCCTGAGCGCCTCCGTGGGAGACAGGGTGACCATCACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTGAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATTTACTACACCAGCAGGCTGGAAACCGGCGTGCCCAGCAGATTTAGCGGCAGCGGCAGCGGCACCGACTTTACCTTTACCATCTCCAGCCTGCAGCCCGAGGATATCGCCACATACTACTGCCAGCAGGGCAACACCCTCCCCCCTACCTTTGGCGGCGGCACCAAGGTGGAGATTAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCA ATGAGAAAGG 1418 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-175AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGTCCGGCCCCGAACTGAAAAAGCCCGGCGCCAGCGTCAAGATCAGCTGCAAGACCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGGCCCCCGGCCAGGGACTGGAATGGATTGGCGACATCTACCCCGACAACTACAACATTAGGTATAACCAGAAGTTCCAGGGCAAGGCCACCATCACAAGAGACACCAGCAGCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACAGTGTCCAGCGGCGGCGGCGGCTCCGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGACATTCAGATGACACAGAGCCCCTCCAGCCTGAGCGCCAGCCTGGGCGATAGGGTGACCATCACCTGCAGAACCAGCCAGGACATCAGCAACCACCTGAATTGGTACCAGCAGAAGCCCGGAAAGGCCCCCAAACTGCTGATCTACTACACCAGCAGGCTGGAGAGCGGCGTGCCTAGCAGGTTTAGCGGCAGCGGCAGCGGCACAGATTACAGCCTGACCATCAGCAGCCTGCAGCCCGAAGACATCGGCACCTACTACTGCCAGCAGGGCAACACCCTGCCCCCTACCTTTGGCGGAGGCACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAAT GAGAAAGG 1419 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-176AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCCAGATGACACAGAGCCCTAGCAGCCTGAGCGCTTCCGTGGGCGACAGGGTGACCATCACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTCAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCTCCAGGCTGGAGACCGGAGTGCCCTCCAGATTTTCCGGCAGCGGCAGCGGCACCGATTTCACCTTCACCATCAGCAGCCTGCAGCCCGAGGACATCGCCACCTACTATTGCCAGCAGGGCAACACCCTGCCCCCCACATTTGGAGGCGGCACCAAGGTGGAGATCAAGGGCGGAGGAGGAAGCGGAGGAGGAGGAAGCGGAGGAGGCGGAAGCCAGGTGCAGCTGGTGCAGAGCGGCGCTGAGCTCAAGAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAAGCCTCCGGATACACCTTCACCGAGTACACCATCAATTGGGTGAGACAGGCCCCCGGCCAAAGACTGGAGTGGATGGGCGACATCTATCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGAGACACCAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAATCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACCGTCAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCA ATGAGAAAGG 1420 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-177AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGATATCCAGATGACACAGAGCCCTAGCTCCCTGAGCGCCAGCCTGGGCGATAGGGTGACCATCACCTGCAGGACCTCCCAGGACATCAGCAACCACCTGAACTGGTACCAGCAGAAGCCCGGCAAAGCCCCCAAGCTGCTGATCTACTACACCAGCAGGCTGGAAAGCGGCGTGCCCAGCAGGTTTAGCGGAAGCGGCAGCGGCACCGACTACAGCCTGACCATCAGCTCCCTGCAGCCCGAGGACATCGGCACCTACTACTGCCAGCAGGGCAACACCCTGCCTCCCACCTTCGGAGGCGGAACCAAGCTGGAGATTAAGGGAGGCGGCGGAAGCGGCGGCGGCGGCTCCGGCGGAGGAGGCAGCCAGGTGCAGCTGGTGCAGTCCGGAGCCGAGCTGAAAAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAGGCCAGCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAGGCAGGCCCCTGGCCAGAGACTCGAGTGGATGGGCGACATCTACCCCGACAACTACTCCATCAGGTACAACCAGAAGTTTCAGGGCAGGGTGACCATTACCAGGGACACCAGCGCCAGCACAGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGATACAGCCGTCTACTACTGCGCCAACCACGACTTTTTCGTGTTCTGGGGACAGGGCACCCTGGTGACCGTGTCCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCA ATGAGAAAGG 1421 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-178AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGACATCCAAATGACCCAGAGCCCTAGCTCCCTGAGCGCTTCCGTGGGCGACAGAGTGACCATTACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTGAACTGGTATCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTACTACACCAGCAGGCTGGAGACCGGAGTGCCCAGCAGGTTTAGCGGCTCCGGATCCGGCACCGACTTCACCTTCACCATCTCCAGCCTGCAGCCCGAGGACATCGCCACCTACTACTGCCAGCAGGGCAATACCCTCCCCCCTACCTTCGGAGGCGGCACCAAGGTGGAGATCAAGGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGGCGGAGGCGGCAGCCAGGTGCAACTGGTGCAGAGCGGCCCTGAGCTGAAGAAACCCGGCGCCAGCGTGAAAATCAGCTGCAAGACCAGCGGCTACACATTCACCGAGTACACCATCAACTGGGTGAAGCAGGCTCCCGGACAGGGACTGGAGTGGATCGGCGACATCTACCCTGACAACTACAACATCAGATACAACCAAAAGTTCCAGGGCAAGGCCACCATCACCAGGGACACCAGCTCCTCCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACCGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCAAT GAGAAAGG 1422 LHA to RHA ofGAGATGTAAGGAGCTGCTGTGACTTGCTCAAGGCCTTATATCG CTX-179AGTAAACGGTAGTGCTGGGGCTTAGACGCAGGTGTTCTGATTTATAGTTCAAAACCTCTATCAATGAGAGAGCAATCTCCTGGTAATGTGATAGATTTCCCAACTTAATGCCAACATACCATAAACCTCCCATTCTGCTAATGCCCAGCCTAAGTTGGGGAGACCACTCCAGATTCCAAGATGTACAGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTTATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTATTATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGCCGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGCCTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTTCCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTTGTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATGAGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGCTAGACATGAGGTCTATGGACTTCAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACCACCATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTTGCTCCACGCAGCAAGGCCGGATATCCAGATGACACAAAGCCCCAGCAGCCTGTCCGCTAGCCTGGGCGATAGGGTGACCATCACATGCAGGACCAGCCAGGACATCTCCAACCACCTGAACTGGTACCAGCAGAAGCCTGGAAAGGCCCCCAAACTGCTGATCTACTACACCAGCAGGCTGGAGAGCGGCGTGCCTAGCAGGTTTTCCGGCAGCGGCAGCGGCACCGACTATAGCCTGACCATCAGCTCCCTGCAGCCCGAGGACATCGGCACCTACTACTGCCAGCAGGGAAACACACTGCCCCCCACCTTTGGCGGCGGCACAAAGCTGGAGATCAAGGGCGGCGGCGGATCCGGCGGCGGAGGCAGCGGAGGAGGAGGAAGCCAGGTGCAGCTGGTGCAGTCCGGCCCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAAATTAGCTGCAAGACCTCCGGCTACACATTCACCGAGTACACCATCAACTGGGTGAAGCAGGCTCCCGGCCAGGGACTGGAGTGGATCGGCGACATCTACCCCGACAACTACAACATCAGGTACAACCAGAAATTCCAGGGCAAGGCCACCATCACCAGGGACACCAGCTCCTCCACCGCCTATATGGAGCTGTCCAGCCTGAGAAGCGAGGATACCGCCGTGTACTACTGCGCCAACCACGATTTCTTCGTGTTCTGGGGCCAGGGCACACTGGTCACCGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGATAATAATAAAATCGCTATCCATCGAAGATGGATGTGTGTTGGTTTTTTGTGTGTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGGCTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATGATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCACCAAAACCCTCTTTTTACTAAGAAACAGTGAGCCTTGTTCTGGCAGTCCAGAGAATGACACGGGAAAAAAGCAGATGAAGAGAAGGTGGCAGGAGAGGGCACGTGGCCCAGCCTCAGTCTCTCCAACTGAGTTCCTGCCTGCCTGCCTTTGCTCAGACTGTTTGCCCCTTACTGCTCTTCTAGGCCTCATTCTAAGCCCCTTCTCCAAGTTGCCTCTCCTTATTTCTCCCTGTCTGCCAAAAAATCTTTCCCAGCTCACTAAGTCAGTCTCACGCAGTCACTCATTAACCCACCAATCACTGATTGTGCCGGCACATGAATGCACCAGGTGTTGAAGTGGAGGAATTAAAAAGTCAGATGAGGGGTGTGCCCAGAGGAAGCACCATTCTAGTTGGGGGAGCCCATCTGTCAGCTGGGAAAAGTCCAAATAACTTCAGATTGGAATGTGTTTTAACTCAGGGTTGAGAAAACAGCTACCTTCAGGACAAAAGTCAGGGAAGGGCTCTCTGAAGAAATGCTACTTGAAGATACCAGCCCTACCAAGGGCAGGGAGAGGACCCTATAGAGGCCTGGGACAGGAGCTCA ATGAGAAAGG

TABLE 36 CAR Nucleotide Sequences SEQ ID NO: Description Sequence 1316Anti-CD19 ATGCTTCTTTTGGTTACGTCTCTGTTGCTTTGCGAACTTCCTCAT CAR of CTX-CCAGCGTTCTTGCTGATCCCCGATATTCAGATGACTCAGACCAC 131 to CTX-CAGTAGCTTGTCTGCCTCACTGGGAGACCGAGTAACAATCTCC 141TGCAGGGCAAGTCAAGACATTAGCAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTAAAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGTAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCT CCCAGA 1423 Anti-CD70AATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGATATAGTTATGACCCAATCACCC 142GATAGTCTTGCGGTAAGCCTGGGGGAGCGAGCAACAATAAACTGTCGGGCATCAAAATCCGTCAGTACAAGCGGGTATTCATTCATGCACTGGTATCAACAGAAACCCGGTCAGCCACCCAAGCTCCTGATTTATCTTGCGTCTAATCTTGAGTCCGGCGTCCCAGACCGGTTTTCCGGCTCCGGGAGCGGCACGGATTTTACTCTTACTATTTCTAGCCTTCAGGCCGAAGATGTGGCGGTATACTACTGCCAGCATTCAAGGGAAGTTCCTTGGACGTTCGGTCAGGGCACGAAAGTGGAAATTAAAGGCGGGGGGGGATCCGGCGGGGGAGGGTCTGGAGGAGGTGGCAGTGGTCAGGTCCAACTGGTGCAGTCCGGGGCAGAGGTAAAAAAACCCGGCGCGTCTGTTAAGGTTTCATGCAAGGCCAGTGGATATACTTTCACCAATTACGGAATGAACTGGGTGAGGCAGGCCCCTGGTCAAGGCCTGAAATGGATGGGATGGATAAACACGTACACCGGTGAACCTACCTATGCCGATGCCTTTAAGGGTCGGGTTACGATGACGAGAGACACCTCCATATCAACAGCCTACATGGAGCTCAGCAGATTGAGGAGTGACGATACGGCAGTCTATTACTGTGCAAGAGACTACGGCGATTATGGCATGGATTACTGGGGCCAGGGCACTACAGTAACCGTTTCCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGC CTCCCAGA 1424 Anti-CD70BATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTCCAGTTGGTGCAAAGCGGG 145GCGGAGGTGAAAAAACCCGGCGCTTCCGTGAAGGTGTCCTGTAAGGCGTCCGGTTATACGTTCACGAACTACGGGATGAATTGGGTTCGCCAAGCGCCGGGGCAGGGACTGAAATGGATGGGGTGGATAAATACCTACACCGGCGAACCTACATACGCCGACGCTTTTAAAGGGCGAGTCACTATGACGCGCGATACCAGCATATCCACCGCATACATGGAGCTGTCCCGACTCCGGTCAGACGACACGGCTGTCTACTATTGTGCTCGGGACTATGGCGATTATGGCATGGACTACTGGGGTCAGGGTACGACTGTAACAGTTAGTAGTGGTGGAGGCGGCAGTGGCGGGGGGGGAAGCGGAGGAGGGGGTTCTGGTGACATAGTTATGACCCAATCCCCAGATAGTTTGGCGGTTTCTCTGGGCGAGAGGGCAACGATTAATTGTCGCGCATCAAAGAGCGTTTCAACGAGCGGATATTCTTTTATGCATTGGTACCAGCAAAAACCCGGACAACCGCCGAAGCTGCTGATCTACTTGGCTTCAAATCTTGAGTCTGGGGTGCCGGACCGATTTTCTGGTAGTGGAAGCGGAACTGACTTTACGCTCACGATCAGTTCACTGCAGGCTGAGGATGTAGCGGTCTATTATTGCCAGCACAGTAGAGAAGTCCCCTGGACCTTCGGTCAAGGCACGAAAGTAGAAATTAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCC TGCCTCCCAGA 1275 Anti-CD70ATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTCCAGTTGGTGCAAAGCGGG 145bGCGGAGGTGAAAAAACCCGGCGCTTCCGTGAAGGTGTCCTGTAAGGCGTCCGGTTATACGTTCACGAACTACGGGATGAATTGGGTTCGCCAAGCGCCGGGGCAGGGACTGAAATGGATGGGGTGGATAAATACCTACACCGGCGAACCTACATACGCCGACGCTTTTAAAGGGCGAGTCACTATGACGCGCGATACCAGCATATCCACCGCATACATGGAGCTGTCCCGACTCCGGTCAGACGACACGGCTGTCTACTATTGTGCTCGGGACTATGGCGATTATGGCATGGACTACTGGGGTCAGGGTACGACTGTAACAGTTAGTAGTGGTGGAGGCGGCAGTGGCGGGGGGGGAAGCGGAGGAGGGGGTTCTGGTGACATAGTTATGACCCAATCCCCAGATAGTTTGGCGGTTTCTCTGGGCGAGAGGGCAACGATTAATTGTCGCGCATCAAAGAGCGTTTCAACGAGCGGATATTCTTTTATGCATTGGTACCAGCAAAAACCCGGACAACCGCCGAAGCTGCTGATCTACTTGGCTTCAAATCTTGAGTCTGGGGTGCCGGACCGATTTTCTGGTAGTGGAAGCGGAACTGACTTTACGCTCACGATCAGTTCACTGCAGGCTGAGGATGTAGCGGTCTATTATTGCCAGCACAGTAGAGAAGTCCCCTGGACCTTCGGTCAAGGCACGAAAGTAGAAATTAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATA TGCAGGCCCTGCCTCCCAGATAA 1425Anti-BCMA-1 ATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTG CAR of CTXCTTCATGCTGCTAGACCTCAGGTGCAGTTACAACAGTCAGGAG 152 and CTX-GAGGATTAGTGCAGCCAGGAGGATCTCTGAAACTGTCTTGTGC 153CGCCAGCGGAATCGATTTTAGCAGGTACTGGATGTCTTGGGTGAGAAGAGCCCCTGGAAAAGGACTGGAGTGGATCGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGTCTTCTGGAGGAGGAGGATCCGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGAGATATTGTGATGACACAAAGCCAGCGGTTCATGACCACATCTGTGGGCGACAGAGTGAGCGTGACCTGTAAAGCTTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCCAGACAGAGCCCTAAAGCCCTGATCTTTTCTGCCAGCCTGAGATTTTCTGGCGTTCCTGCCAGATTTACCGGCTCTGGCTCTGGCACCGATTTTACACTGACCATCAGCAATCTGCAGTCTGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAACTACCCCCTGACCTTTGGAGCTGGCACAAAACTGGAGCTGAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCA GA 1426 Anti-BCMA-2ATGGCTCTTCCTGTAACCGCACTTCTGCTTCCTCTTGCTCTGCTG CAR of CTX-CTTCATGCTGCTAGACCTGACATCGTGATGACCCAAAGCCAGA 154 and CTX-GGTTCATGACCACATCTGTGGGCGATAGAGTGAGCGTGACCTG 155TAAAGCCTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCTAGACAGAGCCCTAAAGCCCTGATCTTTAGCGCCAGCCTGAGATTTAGCGGAGTTCCTGCCAGATTTACCGGAAGCGGATCTGGAACCGATTTTACACTGACCATCAGCAACCTGCAGAGCGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAATTACCCTCTGACCTTTGGAGCCGGCACAAAGCTGGAGCTGAAAGGAGGAGGAGGATCTGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGACAAGTTCAATTACAGCAATCTGGAGGAGGACTGGTTCAGCCTGGAGGAAGCCTGAAGCTGTCTTGTGCCGCTTCTGGAATCGATTTTAGCAGATACTGGATGAGCTGGGTGAGAAGAGCCCCTGGCAAAGGACTGGAGTGGATTGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCC CAGA 1427 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGAGGTCCAGCTGGTGGAGAGCGG 160CGGAGGACTGGTCCAGCCTGGCGGCTCCCTGAAACTGAGCTGCGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAATGGATCGGCGAGATCAACCCCGACTCCAGCACCATCAACTACGCCGACAGCGTCAAGGGCAGGTTCACCATTAGCAGGGACAATGCCAAGAACACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAAGACACCGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCTCCGGAGGAGGCGGCAGCGGCGGAGGCGGCAGCGGCGGAGGCGGCAGCGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCTCCGTGGGAGATAGGGTGACAATCACCTGTAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTATCAACAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTTTCCGCCTCCCTGAGGTTCAGCGGAGTCCCCAGCAGGTTCTCCGGATCCGGCTCCGGAACCGACTTTACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAGCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTC CCAGA 1428 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGAGGTCCAGCTGGTGGAGAGCGG 160bCGGAGGACTGGTCCAGCCTGGCGGCTCCCTGAAACTGAGCTGCGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAATGGATCGGCGAGATCAACCCCGACTCCAGCACCATCAACTACGCCGACAGCGTCAAGGGCAGGTTCACCATTAGCAGGGACAATGCCAAGAACACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAAGACACCGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCTCCGGAGGAGGCGGCAGCGGCGGAGGCGGCAGCGGCGGAGGCGGCAGCGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCTCCGTGGGAGATAGGGTGACAATCACCTGTAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTATCAACAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTTTCCGCCTCCCTGAGGTTCAGCGGAGTCCCCAGCAGGTTCTCCGGATCCGGCTCCGGAACCGACTTTACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAGCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCC TGCCTCCCAGA 1429 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGAGGTGCAGCTGGTGGAGAGCGG 161AGGAGGACTGGTGCAGCCCGGAGGCTCCCTGAAGCTGAGCTGCGCTGCCTCCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGGCAGGCTCCCGGCAAAGGCCTGGAGTGGATCGGCGAGATCAACCCCGACAGCAGCACCATCAACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAATACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAGGACACAGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGAGACGCTATGGACTACTGGGGCCAGGGAACCCTGGTGACCGTGAGCAGCGGAGGCGGAGGCTCCGGCGGCGGAGGCAGCGGAGGAGGCGGCAGCGATATCCAGATGACCCAGTCCCCCAGCTCCCTGAGCGCTAGCCCTGGCGACAGGGTGAGCGTGACATGCAAGGCCAGCCAGAGCGTGGACAGCAACGTGGCCTGGTACCAGCAGAAACCCAGACAGGCCCCCAAGGCCCTGATCTTCAGCGCCAGCCTGAGGTTTAGCGGCGTGCCCGCTAGGTTTACCGGATCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCAACCTGCAGTCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAACTACCCCCTGACATTCGGCGCCGGAACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCC TCCCAGA 1430 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGACATCCAGATGACCCAGAGCCCT 162AGCAGCCTGAGCGCTAGCGTGGGCGACAGGGTGACCATCACCTGCAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTACCAGCAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTCAGCGCCAGCCTGAGGTTCTCCGGAGTGCCTAGCAGATTTAGCGGCAGCGGCAGCGGCACAGACTTCACCCTGACCATCAGCAGCCTCCAGCCCGAGGATTTCGCCACCTACTACTGCCAGCAGTACAACTCCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGGGAGGAGGAGGAAGCGGAGGAGGAGGAAGCGGAGGCGGAGGAAGCGAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGCAACCTGGAGGCAGCCTGAAGCTGAGCTGTGCCGCCAGCGGAATCGACTTCAGCAGGTACTGGATGTCCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAGTGGATCGGAGAGATCAACCCCGACAGCTCCACCATCAACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGAGACAACGCCAAGAACACCCTGTACCTGCAGATGAACCTGTCCAGAGCCGAGGACACCGCCCTGTACTACTGCGCCAGCCTGTATTACGACTACGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCC CAGA 1431 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGACATCCAAATGACCCAGTCCCCT 163AGCAGCCTGTCCGCCAGCCCTGGAGACAGGGTGTCCGTGACCTGCAAGGCCAGCCAGTCCGTGGACAGCAACGTCGCCTGGTATCAGCAGAAGCCCAGGCAAGCTCCCAAGGCTCTGATCTTCTCCGCCAGCCTGAGATTTTCCGGCGTGCCCGCCAGATTCACCGGAAGCGGCAGCGGCACCGACTTCACCCTGACCATCAGCAACCTGCAGAGCGAGGATTTCGCCACATACTACTGCCAGCAGTACAACAACTACCCCCTGACCTTCGGAGCCGGCACCAAGCTGGAGATCAAAGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGATCCGAAGTGCAGCTGGTGGAAAGCGGAGGCGGACTCGTGCAGCCTGGCGGAAGCCTGAAGCTGAGCTGTGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGGCAGGCTCCCGGCAAAGGCCTGGAGTGGATCGGCGAGATCAACCCTGACAGCAGCACCATCAACTACGCCGACAGCGTGAAAGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACACCCTGTACCTGCAGATGAACCTGTCCAGAGCCGAGGACACCGCCCTGTACTACTGCGCCAGCCTGTACTACGACTACGGCGACGCTATGGACTACTGGGGCCAAGGCACCCTCGTGACCGTCAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTC CCAGA 1432 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGAGGTGCAGCTGCAGCAGTCCGGC 164CCTGAGCTCGTGAAGCCTGGAGCCAGCGTGAAAATGAGCTGTAAGGCCTCCGGCAACACCCTCACCAACTACGTGATCCATTGGATGAAGCAGATGCCCGGCCAGGGCCTGGACTGGATTGGCTACATTCTGCCCTACAACGACCTGACCAAGTACAACGAGAAGTTCACCGGCAAGGCCACCCTGACCAGCGATAAGAGCTCCAGCAGCGCCTACATGGAGCTGAACTCCCTGACCAGCGAGGACAGCGCCGTGTACTACTGCACCAGGTGGGACTGGGATGGCTTCTTCGACCCCTGGGGACAGGGCACCACCCTGACAGTGTCCAGCGGAGGAGGCGGCAGCGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGATATCGTGATGACACAGTCCCCTCTGAGCCTGCCTGTGAGCCTGGGCGACCAGGCCAGCATCAGCTGCAGGTCCACCCAGTCCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTACCTGCAAAGGCCCGGCCAGTCCCCTAAGCTGCTGATCTACAGCGTGAGCAACAGGTTTAGCGAGGTGCCCGATAGATTTTCCGCCAGCGGCAGCGGCACCGACTTCACACTGAAGATCTCCAGGGTGGAGGCCGAGGATCTGGGCGTGTACTTCTGCAGCCAGACCAGCCACATCCCCTACACCTTCGGCGGCGGAACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGC CCTGCCTCCCAGA 1433 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGACATCGTGATGACCCAGAGCCCC 165CTGAGCCTGCCTGTGTCCCTGGGAGACCAGGCTTCCATCAGCTGCAGGTCCACCCAGAGCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTACCTGCAGAGGCCTGGCCAGTCCCCCAAGCTGCTGATCTACAGCGTGAGCAATAGGTTCAGCGAGGTGCCCGACAGATTCAGCGCCAGCGGAAGCGGCACCGACTTCACCCTGAAGATCAGCAGGGTCGAGGCCGAAGATCTGGGCGTGTACTTCTGCTCCCAGACATCCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATTAAGGGCGGCGGAGGATCCGGCGGAGGAGGATCCGGAGGAGGAGGAAGCGAGGTGCAGCTGCAGCAGAGCGGACCCGAGCTGGTGAAACCCGGAGCCAGCGTCAAAATGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTCATCCACTGGATGAAGCAGATGCCCGGACAGGGCCTGGACTGGATCGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAACGAGAAATTCACCGGCAAGGCCACCCTGACCAGCGACAAGAGCAGCAGCAGCGCCTACATGGAGCTGAACAGCCTGACCAGCGAGGACTCCGCCGTGTACTATTGCACCAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACACTCACCGTGAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAG GCCCTGCCTCCCAGA 1434Anti-BCMA ATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGG 166AGCCGAGCTCAAGAAGCCCGGAGCCTCCGTGAAGGTGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAAGCCCCCGGCCAAAGGCTGGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCTCCACCGCCTATATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGTACAAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACAGTGACCGTCAGCAGCGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGAAGCGAAATCGTGATGACCCAGAGCCCCGCCACACTGAGCGTGAGCCCTGGCGAGAGGGCCAGCATCTCCTGCAGGGCTAGCCAAAGCCTGGTGCACAGCAACGGCAACACCCACCTGCACTGGTACCAGCAGAGACCCGGACAGGCTCCCAGGCTGCTGATCTACAGCGTGAGCAACAGGTTCTCCGAGGTGCCTGCCAGGTTTAGCGGCAGCGGAAGCGGCACCGACTTTACCCTGACCATCAGCAGCGTGGAGTCCGAGGACTTCGCCGTGTATTACTGCAGCCAGACCAGCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGG CCCTGCCTCCCAGA 1435Anti-BCMA ATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGG 166bAGCCGAGCTCAAGAAGCCCGGAGCCTCCGTGAAGGTGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAAGCCCCCGGCCAAAGGCTGGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCTCCACCGCCTATATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGTACAAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACAGTGACCGTCAGCAGCGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGAAGCGAAATCGTGATGACCCAGAGCCCCGCCACACTGAGCGTGAGCCCTGGCGAGAGGGCCAGCATCTCCTGCAGGGCTAGCCAAAGCCTGGTGCACAGCAACGGCAACACCCACCTGCACTGGTACCAGCAGAGACCCGGACAGGCTCCCAGGCTGCTGATCTACAGCGTGAGCAACAGGTTCTCCGAGGTGCCTGCCAGGTTTAGCGGCAGCGGAAGCGGCACCGACTTTACCCTGACCATCAGCAGCGTGGAGTCCGAGGACTTCGCCGTGTATTACTGCAGCCAGACCAGCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCA TATGCAGGCCCTGCCTCCCAGA 1436Anti-BCMA ATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGG 167CGCCGAGCTGAAGAAACCTGGCGCCAGCGTCAAGGTGAGCTGCAAGGCTTCCGGAAACACCCTCACCAACTACGTGATCCACTGGGTGAGGCAGGCCCCCGGACAGAGACTGGAGTGGATGGGCTACATTCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTCACCATCACCAGGGACAAGAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGTCCGAGGACACAGCCGTGTACTACTGCACCAGGTGGGACTGGGACGGATTCTTCGACCCTTGGGGCCAAGGCACCACAGTGACAGTGAGCTCCGGCGGAGGCGGCAGCGGCGGCGGAGGAAGCGGCGGCGGCGGAAGCGACATCGTGATGACCCAGAGCCCTCTGAGCCTGCCCGTGACACTGGGACAGCCTGCCACACTGTCCTGCAGGAGCACCCAGAGCCTGGTGCATAGCAACGGCAACACCCACCTGCACTGGTTCCAGCAGAGACCTGGCCAGAGCCCCCTGAGACTGATCTACAGCGTGAGCAACAGGGACAGCGGCGTGCCCGATAGATTTAGCGGCAGCGGCAGCGGCACCGACTTTACCCTGAAAATCTCCAGGGTGGAGGCCGAGGATGTGGGCGTGTATTACTGCTCCCAGACAAGCCACATTCCCTATACATTCGGCGGCGGCACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAG GCCCTGCCTCCCAGA 1437Anti-BCMA ATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGAAATCGTGATGACCCAGAGCCCT 168GCCACACTGAGCGTGAGCCCTGGCGAGAGAGCCAGCATCAGCTGCAGGGCCTCCCAGAGCCTGGTGCACTCCAACGGCAATACCCACCTGCACTGGTATCAGCAGAGACCCGGCCAGGCCCCTAGGCTGCTGATCTACTCCGTGAGCAACAGGTTCTCCGAGGTGCCCGCCAGATTCAGCGGATCCGGCAGCGGCACCGACTTCACCCTCACCATCTCCAGCGTGGAGAGCGAGGACTTCGCCGTCTACTACTGCAGCCAGACAAGCCACATCCCCTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGGGCGGCGGCGGCAGCGGCGGCGGAGGCAGCGGAGGCGGCGGATCCCAGGTGCAACTGGTGCAGAGCGGAGCCGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGGTCAGCTGCAAGGCCAGCGGCAACACCCTGACAAACTACGTGATCCACTGGGTGAGGCAGGCCCCTGGCCAAAGGCTCGAGTGGATGGGCTACATCCTCCCCTACAACGACCTGACCAAGTACTCCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCAGCACCGCCTACATGGAACTCAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCACCAGGTGGGACTGGGATGGCTTCTTCGACCCTTGGGGCCAGGGCACCACCGTGACAGTGAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAG GCCCTGCCTCCCAGA 1438Anti-BCMA ATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGACATCGTGATGACACAATCCCCC 169CTCAGCCTGCCTGTGACACTGGGCCAGCCTGCCACCCTGAGCTGCAGGAGCACCCAGTCCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTTCCAGCAGAGGCCTGGACAGAGCCCCCTGAGGCTGATCTACAGCGTGAGCAACAGGGACTCCGGCGTGCCCGATAGATTCAGCGGCAGCGGCTCCGGCACCGATTTCACCCTGAAGATCTCCAGAGTGGAAGCCGAGGACGTGGGCGTCTACTACTGCAGCCAGACCAGCCATATCCCCTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGGGAGGCGGCGGAAGCGGCGGAGGCGGATCCGGAGGCGGAGGCTCCCAAGTGCAGCTGGTGCAGAGCGGCGCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGAAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAGGCCCCCGGACAGAGACTCGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGACAAGAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTGTACTACTGCACCAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGAACCACAGTGACCGTGTCCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAG GCCCTGCCTCCCAGA 1439Anti-BCMA ATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGAGGTGCAGCTGCAGCAGAGCGG 170CCCTGAGCTGGTGAAGCCCGGCGCCAGCGTGAAGATCAGCTGCAAGACCTCCGGCTATACCTTTACCGAGTACACCATCAACTGGGTGAAGCAGAGCCACGGCAAGAGCCTGGAGTGGATCGGCGATATCTACCCCGACAACTACAACATCAGGTACAACCAGAAGTTCAAGGGCAAGGCCACCCTGACCGTGGACAAGTCCAGCAGCACCGCCTACATGGAGCTGAGGAGCCTGTCCAGCGAGGACTCCGCCATCTACTACTGCGCCAACCACGACTTTTTCGTCTTCTGGGGACAGGGCACCCTGGTGACAGTGTCCGCTGGCGGCGGCGGCAGCGGCGGCGGCGGCTCCGGAGGCGGCGGCAGCGACATCCAGATGACACAGGCCACAAGCTCCCTGTCCGCCAGCCTGGGCGATAGGGTGACCATCAATTGCAGGACCTCCCAGGACATCAGCAACCACCTGAACTGGTACCAGCAGAAACCCGACGGCACCGTGAAGCTGCTCATCTACTACACCAGCAGGCTGCAGTCCGGCGTCCCTAGCAGATTCAGCGGATCCGGCAGCGGCACCGACTATAGCCTGACCATCAGCAACCTCGAGCAGGAGGACATCGGCACCTACTTCTGCCATCAGGGCAACACCCTGCCCCCTACCTTTGGCGGCGGCACAAAGCTGGAGATTAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1440 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGATATCCAGATGACCCAGGCCACC 171AGCAGCCTGAGCGCTTCCCTCGGCGACAGGGTGACCATCAACTGCAGGACCAGCCAGGACATCTCCAACCACCTGAACTGGTACCAGCAGAAGCCCGACGGCACCGTGAAACTGCTGATCTACTACACCAGCAGACTGCAGAGCGGCGTGCCCTCCAGATTTTCCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATTAGCAACCTGGAGCAGGAGGACATCGGAACCTACTTCTGCCACCAGGGCAACACACTGCCTCCCACCTTCGGCGGCGGCACAAAGCTCGAGATCAAGGGCGGCGGCGGAAGCGGCGGCGGCGGCAGCGGCGGCGGAGGCTCCGAGGTGCAACTGCAACAGAGCGGACCTGAGCTGGTGAAGCCTGGCGCCAGCGTGAAGATCTCCTGTAAGACCAGCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGAGCCACGGCAAGAGCCTCGAATGGATCGGCGACATCTATCCCGACAACTACAATATCAGATACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGTGGATAAGTCCTCCTCCACCGCTTACATGGAGCTGAGGAGCCTGAGCAGCGAGGACTCCGCCATCTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAAGGCACCCTCGTGACCGTGAGCGCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1441 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGTCCGGC 172GCTGAGCTGAAGAAGCCCGGCGCCAGCGTGAAGATCAGCTGCAAGGCCAGCGGCTACACCTTCACCGAATACACCATCAACTGGGTGAGACAGGCCCCTGGACAGAGGCTCGAGTGGATGGGCGACATCTACCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGACACCAGCGCCAGCACCGCCTATATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTCTATTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACACTGGTGACCGTGTCCAGCGGCGGCGGCGGCAGCGGCGGCGGAGGAAGCGGCGGCGGCGGCAGCGATATCCAGATGACCCAGAGCCCCTCCTCCCTGAGCGCTAGCGTGGGCGACAGGGTGACCATTACCTGTCAGGCCTCCCAGGACATCAGCAACTACCTGAACTGGTACCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTATTACACCAGCAGGCTGGAGACCGGCGTGCCCTCCAGATTCAGCGGCTCCGGCTCCGGAACCGACTTCACCTTCACCATCAGCTCCCTGCAGCCTGAGGACATCGCCACCTACTACTGCCAGCAGGGCAACACCCTGCCTCCCACATTCGGCGGCGGCACAAAGGTGGAGATCAAAAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1442 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTCCAGTCCGGC 173GCCGAACTGAAGAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAGGCCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAGGCAAGCCCCCGGCCAGAGACTGGAGTGGATGGGCGACATCTACCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGATACCAGCGCCAGCACAGCCTATATGGAGCTGTCCTCCCTGAGATCCGAGGACACCGCCGTGTATTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAAGGCACCCTGGTGACCGTGAGCAGCGGCGGCGGCGGCTCCGGCGGCGGAGGCTCCGGAGGCGGAGGCAGCGACATCCAGATGACCCAGAGCCCTTCCAGCCTGAGCGCTAGCCTGGGCGACAGGGTGACCATCACCTGCAGGACCAGCCAGGACATCAGCAATCACCTGAACTGGTACCAGCAAAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCAGCAGGCTGGAAAGCGGCGTGCCTAGCAGGTTCAGCGGCAGCGGCTCCGGAACCGACTACAGCCTGACCATTAGCAGCCTGCAACCTGAGGACATCGGCACCTATTACTGCCAGCAGGGCAACACCCTGCCTCCTACCTTTGGCGGCGGCACCAAACTCGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1443 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGAGCGG 174CCCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGATCTCCTGCAAGACCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGGCCCCCGGACAGGGACTGGAATGGATCGGCGACATCTACCCCGACAACTACAACATCAGGTACAACCAGAAGTTCCAAGGCAAGGCCACCATCACAAGGGACACCAGCAGCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGATACCGCCGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCGGAGGAGGCGGAAGCGGAGGAGGAGGATCCGGAGGAGGAGGCAGCGACATCCAGATGACCCAGTCCCCCTCCTCCCTGAGCGCCTCCGTGGGAGACAGGGTGACCATCACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTGAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATTTACTACACCAGCAGGCTGGAAACCGGCGTGCCCAGCAGATTTAGCGGCAGCGGCAGCGGCACCGACTTTACCTTTACCATCTCCAGCCTGCAGCCCGAGGATATCGCCACATACTACTGCCAGCAGGGCAACACCCTCCCCCCTACCTTTGGCGGCGGCACCAAGGTGGAGATTAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1444 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGCAGGTGCAGCTGGTGCAGTCCGGC 175CCCGAACTGAAAAAGCCCGGCGCCAGCGTCAAGATCAGCTGCAAGACCTCCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGGCCCCCGGCCAGGGACTGGAATGGATTGGCGACATCTACCCCGACAACTACAACATTAGGTATAACCAGAAGTTCCAGGGCAAGGCCACCATCACAAGAGACACCAGCAGCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACAGTGTCCAGCGGCGGCGGCGGCTCCGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGACATTCAGATGACACAGAGCCCCTCCAGCCTGAGCGCCAGCCTGGGCGATAGGGTGACCATCACCTGCAGAACCAGCCAGGACATCAGCAACCACCTGAATTGGTACCAGCAGAAGCCCGGAAAGGCCCCCAAACTGCTGATCTACTACACCAGCAGGCTGGAGAGCGGCGTGCCTAGCAGGTTTAGCGGCAGCGGCAGCGGCACAGATTACAGCCTGACCATCAGCAGCCTGCAGCCCGAAGACATCGGCACCTACTACTGCCAGCAGGGCAACACCCTGCCCCCTACCTTTGGCGGAGGCACCAAGCTGGAGATCAAGAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1445 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGACATCCAGATGACACAGAGCCCT 176AGCAGCCTGAGCGCTTCCGTGGGCGACAGGGTGACCATCACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTCAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCTCCAGGCTGGAGACCGGAGTGCCCTCCAGATTTTCCGGCAGCGGCAGCGGCACCGATTTCACCTTCACCATCAGCAGCCTGCAGCCCGAGGACATCGCCACCTACTATTGCCAGCAGGGCAACACCCTGCCCCCCACATTTGGAGGCGGCACCAAGGTGGAGATCAAGGGCGGAGGAGGAAGCGGAGGAGGAGGAAGCGGAGGAGGCGGAAGCCAGGTGCAGCTGGTGCAGAGCGGCGCTGAGCTCAAGAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAAGCCTCCGGATACACCTTCACCGAGTACACCATCAATTGGGTGAGACAGGCCCCCGGCCAAAGACTGGAGTGGATGGGCGACATCTATCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGAGACACCAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAATCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACCGTCAGCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1446 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGATATCCAGATGACACAGAGCCCT 177AGCTCCCTGAGCGCCAGCCTGGGCGATAGGGTGACCATCACCTGCAGGACCTCCCAGGACATCAGCAACCACCTGAACTGGTACCAGCAGAAGCCCGGCAAAGCCCCCAAGCTGCTGATCTACTACACCAGCAGGCTGGAAAGCGGCGTGCCCAGCAGGTTTAGCGGAAGCGGCAGCGGCACCGACTACAGCCTGACCATCAGCTCCCTGCAGCCCGAGGACATCGGCACCTACTACTGCCAGCAGGGCAACACCCTGCCTCCCACCTTCGGAGGCGGAACCAAGCTGGAGATTAAGGGAGGCGGCGGAAGCGGCGGCGGCGGCTCCGGCGGAGGAGGCAGCCAGGTGCAGCTGGTGCAGTCCGGAGCCGAGCTGAAAAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAGGCCAGCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAGGCAGGCCCCTGGCCAGAGACTCGAGTGGATGGGCGACATCTACCCCGACAACTACTCCATCAGGTACAACCAGAAGTTTCAGGGCAGGGTGACCATTACCAGGGACACCAGCGCCAGCACAGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGATACAGCCGTCTACTACTGCGCCAACCACGACTTTTTCGTGTTCTGGGGACAGGGCACCCTGGTGACCGTGTCCTCCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1447 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGACATCCAAATGACCCAGAGCCCT 178AGCTCCCTGAGCGCTTCCGTGGGCGACAGAGTGACCATTACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTGAACTGGTATCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTACTACACCAGCAGGCTGGAGACCGGAGTGCCCAGCAGGTTTAGCGGCTCCGGATCCGGCACCGACTTCACCTTCACCATCTCCAGCCTGCAGCCCGAGGACATCGCCACCTACTACTGCCAGCAGGGCAATACCCTCCCCCCTACCTTCGGAGGCGGCACCAAGGTGGAGATCAAGGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGGCGGAGGCGGCAGCCAGGTGCAACTGGTGCAGAGCGGCCCTGAGCTGAAGAAACCCGGCGCCAGCGTGAAAATCAGCTGCAAGACCAGCGGCTACACATTCACCGAGTACACCATCAACTGGGTGAAGCAGGCTCCCGGACAGGGACTGGAGTGGATCGGCGACATCTACCCTGACAACTACAACATCAGATACAACCAAAAGTTCCAGGGCAAGGCCACCATCACCAGGGACACCAGCTCCTCCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACCGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA 1448 Anti-BCMAATGGCGCTTCCGGTGACAGCACTGCTCCTCCCCTTGGCGCTGTT CAR of CTX-GCTCCACGCAGCAAGGCCGGATATCCAGATGACACAAAGCCCC 179AGCAGCCTGTCCGCTAGCCTGGGCGATAGGGTGACCATCACATGCAGGACCAGCCAGGACATCTCCAACCACCTGAACTGGTACCAGCAGAAGCCTGGAAAGGCCCCCAAACTGCTGATCTACTACACCAGCAGGCTGGAGAGCGGCGTGCCTAGCAGGTTTTCCGGCAGCGGCAGCGGCACCGACTATAGCCTGACCATCAGCTCCCTGCAGCCCGAGGACATCGGCACCTACTACTGCCAGCAGGGAAACACACTGCCCCCCACCTTTGGCGGCGGCACAAAGCTGGAGATCAAGGGCGGCGGCGGATCCGGCGGCGGAGGCAGCGGAGGAGGAGGAAGCCAGGTGCAGCTGGTGCAGTCCGGCCCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAAATTAGCTGCAAGACCTCCGGCTACACATTCACCGAGTACACCATCAACTGGGTGAAGCAGGCTCCCGGCCAGGGACTGGAGTGGATCGGCGACATCTACCCCGACAACTACAACATCAGGTACAACCAGAAATTCCAGGGCAAGGCCACCATCACCAGGGACACCAGCTCCTCCACCGCCTATATGGAGCTGTCCAGCCTGAGAAGCGAGGATACCGCCGTGTACTACTGCGCCAACCACGATTTCTTCGTGTTCTGGGGCCAGGGCACACTGGTCACCGTGAGCAGCAGTGCTGCTGCCTTTGTCCCGGTATTTCTCCCAGCCAAACCGACCACGACTCCCGCCCCGCGCCCTCCGACACCCGCTCCCACCATCGCCTCTCAACCTCTTAGTCTTCGCCCCGAGGCATGCCGACCCGCCGCCGGGGGTGCTGTTCATACGAGGGGCTTGGACTTCGCTTGTGATATTTACATTTGGGCTCCGTTGGCGGGTACGTGCGGCGTCCTTTTGTTGTCACTCGTTATTACTTTGTATTGTAATCACAGGAATCGCTCAAAGCGGAGTAGGTTGTTGCATTCCGATTACATGAATATGACTCCTCGCCGGCCTGGGCCGACAAGAAAACATTACCAACCCTATGCCCCCCCACGAGACTTCGCTGCGTACAGGTCCCGAGTGAAGTTTTCCCGAAGCGCAGACGCTCCGGCATATCAGCAAGGACAGAATCAGCTGTATAACGAACTGAATTTGGGACGCCGCGAGGAGTATGACGTGCTTGATAAACGCCGGGGGAGAGACCCGGAAATGGGGGGTAAACCCCGAAGAAAGAATCCCCAAGAAGGACTCTACAATGAACTCCAGAAGGATAAGATGGCGGAGGCCTACTCAGAAATAGGTATGAAGGGCGAACGACGACGGGGAAAAGGTCACGATGGCCTCTACCAAGGGTTGAGTACGGCAACCAAAGATACGTACGATGCACTGCATATGCAGGCCCTGCCTCCCAGA

TABLE 37 CAR Amino Acid Sequenes SEQ ID NO: Description Sequence 1338Anti-CD19 MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRA CAR of CTX-SQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTD 131 to CTX-YSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPG 141SGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY DALHMQALPPR 1449 Anti-CD70AMALPVTALLLPLALLLHAARPDIVMTQSPDSLAVSLGERATINCR CAR of CTX-ASKSVSTSGYSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGS 142GSGTDFTLTISSLQAEDVAVYYCQHSREVPWTFGQGTKVEIKGGGGSGGGGSGGGGSGQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLKWMGW1NTYTGEPTYADAFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDYGDYGMDYWGQGTTVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGL STATKDTYDALHMQALPPR 1450Anti-CD70B MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCK CAR of CTX-ASGYTFTNYGMNWVRQAPGQGLKWMGWINTYTGEPTYADAFK 145GRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDYGDYGMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGDIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSREVPWTFGQGTKVEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGL STATKDTYDALHMQALPPR 1276Anti-CD70 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCK CAR of CTX-ASGYTFTNYGMNWVRQAPGQGLKWMGWINTYTGEPTYADAFK 145bGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDYGDYGMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGDIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSREVPWTFGQGTKVEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQG LSTATKDTYDALHMQALPPR 1451Anti-BCMA-1 MALPVTALLLPLALLLHAARPQVQLQQSGGGLVQPGGSLKLSCA CAR of CTXASGIDFSRYWMSWVRRAPGKGLEWIGEINPDSST1NYAPSLKDKFI 152 and CTX-ISRDNAKNTLYLQMSKVRSEDTALYYCASLYYDYGDAMDYWGQ 153GTSVTVSSGGGGSGGGGSGGGGSGDIVMTQSQRFMTTSVGDRVSVTCKASQSVDSNVAWYQQKPRQSPKALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDLAEYFCQQYNNYPLTFGAGTKLELKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK DTYDALHMQALPPR 1452Anti-BCMA-2 MALPVTALLLPLALLLHAARPDIVMTQSQRFMTTSVGDRVSVTCK CAR of CTX-ASQSVDSNVAWYQQKPRQSPKALIFSASLRFSGVPARFTGSGSGT 154 and CTX- DFTLTISNLQSEDLAEYFCQQYNNYPLTFGAGTKLELKGGGGSGG 155GGSGGGGSGQVQLQQSGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRRAPGKGLEWIGEINPDSST1NYAPSLKDKFIISRDNAKNTLYLQMSKVRSEDTALYYCASLYYDYGDAMDYWGQGTSVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD TYDALHMQALPPR 1453 Anti-BCMAMALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLKLSCAA CAR of CTX-SGIDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYADSVKGRFTI 160 and CTX-SRDNAKNTLYLQMNLSRAEDTALYYCASLYYDYGDAMDYWGQ 160bGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVDSNVAWYQQKPEKAPKSLIFSASLRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGAGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY DALHMQALPPR 1454 Anti-BCMAMALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLKLSCAA CAR of CTX-SGIDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYADSVKGRFTI 160bSRDNAKNTLYLQMNLSRAEDTALYYCASLYYDYGDAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVDSNVAWYQQKPEKAPKSLIFSASLRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGAGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY DALHMQALPPR 1455 Anti-BCMAMALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLKLSCAA CAR of CTX-SGIDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYADSVKGRFTI 161SRDNAKNTLYLQMNLSRAEDTALYYCASLYYDYGDAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASPGDRVSVTCKASQSVDSNVAWYQQKPRQAPKALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDFATYYCQQYNNYPLTFGAGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY DALHMQALPPR 1456 Anti-BCMAMALPVTALLLPLALLLHAARPDIQMTQSPSSLSASVGDRVTITCRA CAR of CTX-SQSVDSNVAWYQQKPEKAPKSLIFSASLRFSGVPSRFSGSGSGTDF 162TLTISSLQPEDFATYYCQQYNSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYADSVKGRFTISRDNAKNTLYLQMNLSRAEDTALYYCASLYYDYGDAMDYWGQGTLVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD ALHMQALPPR 1457 Anti-BCMAMALPVTALLLPLALLLHAARPDIQMTQSPSSLSASPGDRVSVTCK CAR of CTX-ASQSVDSNVAWYQQKPRQAPKALIFSASLRFSGVPARFTGSGSGT 163DFTLTISNLQSEDFATYYCQQYNNYPLTFGAGTKLEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRQAPGKGLEWIGE1NPDSSTINYADSVKGRFTISRDNAKNTLYLQMNLSRAEDTALYYCASLYYDYGDAMDYWGQGTLVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT YDALHMQALPPR 1458 Anti-BCMAMALPVTALLLPLALLLHAARPEVQLQQSGPELVKPGASVKMSCK CAR of CTX-ASGNTLTNYVIHWMKQMPGQGLDWIGYILPYNDLTKYNEKFTGK 164ATLTSDKSSSSAYMELNSLTSEDSAVYYCTRWDWDGFFDPWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLPVSLGDQASISCRSTQSLVHSNGNTHLHWYLQRPGQSPKLLIYSVSNRFSEVPDRFSASGSGTDFTLKISRVEAEDLGVYFCSQTSHIPYTFGGGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT YDALHMQALPPR 1459 Anti-BCMAMALPVTALLLPLALLLHAARPDIVMTQSPLSLPVSLGDQASISCRS CAR of CTX-TQSLVHSNGNTHLHWYLQRPGQSPKLLIYSVSNRFSEVPDRFSAS 165GSGTDFTLKISRVEAEDLGVYFCSQTSHIPYTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLQQSGPELVKPGASVKMSCKASGNTLTNYVIHWMKQMPGQGLDWIGYILPYNDLTKYNEKFTGKATLTSDKSSSSAYMELNSLTSEDSAVYYCTRWDWDGFFDPWGQGTTLTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK DTYDALHMQALPPR 1460Anti-BCMA MALPVTALLLPLALLLHAARPQVQLVQSGAELKKPGASVKVSCK CAR of CTX-ASGNTLTNYVIHWVRQAPGQRLEWMGYILPYNDLTKYSQKFQGR 166VTITRDKSASTAYMELSSLRSEDTAVYYCTRWDWDGFFDPWGQGTTVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSVSPGERASISCRASQSLVHSNGNTHLHWYQQRPGQAPRLLIYSVSNRFSEVPARFSGSGSGTDFTLTISSVESEDFAVYYCSQTSHIPYTFGGGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD TYDALHMQALPPR 1461 Anti-BCMAMALPVTALLLPLALLLHAARPQVQLVQSGAELKKPGASVKVSCK CAR of CTX-ASGNTLTNYVIHWVRQAPGQRLEWMGYILPYNDLTKYSQKFQGR 166bVTITRDKSASTAYMELSSLRSEDTAVYYCTRWDWDGFFDPWGQGTTVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSVSPGERASISCRASQSLVHSNGNTHLHWYQQRPGQAPRLLIYSVSNRFSEVPARFSGSGSGTDFTLTISSVESEDFAVYYCSQTSHIPYTFGGGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK DTYDALHMQALPPR 1462Anti-BCMA MALPVTALLLPLALLLHAARPQVQLVQSGAELKKPGASVKVSCK CAR of CTX-ASGNTLTNYVIHWVRQAPGQRLEWMGYILPYNDLTKYSQKFQGR 167VTITRDKSASTAYMELSSLRSEDTAVYYCTRWDWDGFFDPWGQGTTVTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLPVTLGQPATLSCRSTQSLVHSNGNTHLHWFQQRPGQSPLRLIYSVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQTSHIPYTFGGGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT KDTYDALHMQALPPR 1463Anti-BCMA MALPVTALLLPLALLLHAARPEIVMTQSPATLSVSPGERASISCRA CAR of CTX-SQSLVHSNGNTHLHWYQQRPGQAPRLLIYSVSNRFSEVPARFSGS 168GSGTDFTLTISSVESEDFAVYYCSQTSHIPYTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAELKKPGASVKVSCKASGNTLTNYVIHVVVRQAPGQRLEWMGYILPYNDLTKYSQKFQGRVTITRDKSASTAYMELSSLRSEDTAVYYCTRWDWDGFFDPWGQGTTVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK DTYDALHMQALPPR 1464Anti-BCMA MALPVTALLLPLALLLHAARPDIVMTQSPLSLPVTLGQPATLSCRS CAR of CTX-TQSLVHSNGNTHLHWFQQRPGQSPLRLIYSVSNRDSGVPDRFSGS 169GSGTDFTLKISRVEAEDVGVYYCSQTSHIPYTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAELKKPGASVKVSCKASGNTLTNYVIHWVRQAPGQRLEWMGYILPYNDLTKYSQKFQGRVTITRDKSASTAYMELSSLRSEDTAVYYCTRWDWDGFFDPWGQGTTVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT KDTYDALHMQALPPR 1465Anti-BCMA MALPVTALLLPLALLLHAARPEVQLQQSGPELVKPGASVKISCKT CAR of CTX-SGYTFTEYTINWVKQSHGKSLEWIGDIYPDNYNIRYNQKFKGKAT 170LTVDKSSSTAYMELRSLSSEDSAIYYCANHDFFVFVVGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQATSSLSASLGDRVTINCRTSQDISNHLNWYQQKPDGTVKLLIYYTSRLQSGVPSRFSGSGSGTDYSLTISNLEQEDIGTYFCHQGNTLPPTFGGGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIVVAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR 1466 Anti-BCMAMALPVTALLLPLALLLHAARPDIQMTQATSSLSASLGDRVTINCRT CAR of CTX-SQDISNHLNWYQQKPDGTVKLLIYYTSRLQSGVPSRFSGSGSGTD 171YSLTISNLEQEDIGTYFCHQGNTLPPTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLQQSGPELVKPGASVKISCKTSGYTFFEYTINWVKQSHGKSLEWIGDIYPDNYNIRYNQKFKGKATLTVDKSSSTAYMELRSLSSEDSAIYYCANHDFFVFWGQGTLVTVSASAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIVVAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR 1467 Anti-BCMAMALPVTALLLPLALLLHAARPQVQLVQSGAELKKPGASVKISCKA CAR of CTX-SGYTFTEYTINWVRQAPGQRLEWMGDIYPDNYSIRYNQKFQGRV 172TITRDTSASTAYMELSSLRSEDTAVYYCANHDFFVFWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYYTSRLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPPTFGGGTKVEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIVVAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR 1468 Anti-BCMAMALPVTALLLPLALLLHAARPQVQLVQSGAELKKPGASVKISCKA CAR of CTX-SGYTFTEYTINWVRQAPGQRLEWMGDIYPDNYSIRYNQKFQGRV 173TITRDTSASTAYMELSSLRSEDTAVYYCANHDFFVFWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASLGDRVTITCRTSQDISNHLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYSLTISSLQPEDIGTYYCQQGNTLPPTFGGGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIVVAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR 1469 Anti-BCMAMALPVTALLLPLALLLHAARPQVQLVQSGPELKKPGASVKISCKT CAR of CTX-SGYTFTEYTINWVKQAPGQGLEWIGDIYPDNYNIRYNQKFQGKAT 174ITRDTSSSTAYMELSSLRSEDTAVYYCANHDFFVFVVGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYYTSRLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPPTFGGGTKVEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR 1470 Anti-BCMAMALPVTALLLPLALLLHAARPQVQLVQSGPELKKPGASVKISCKT CAR of CTX-SGYTFTEYTINWVKQAPGQGLEWIGDIYPDNYNIRYNQKFQGKAT 175ITRDTSSSTAYMELSSLRSEDTAVYYCANHDFFVFVVGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASLGDRVTITCRTSQDISNHLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYSLTISSLQPEDIGTYYCQQGNTLPPTFGGGTKLEIKSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR 1471 Anti-BCMAMALPVTALLLPLALLLHAARPDIOMTOSPSSLSASVGDRVTITCOA CAR of CTX-SQDISNYLNWYQQKPGKAPKLLIYYTSRLETGVPSRFSGSGSGTDF 176TFTISSLQPEDIATYYCQQGNTLPPTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAELKKPGASVKISCKASGYTFTEYTINWVRQAPGQRLEWMGDIYPDNYSIRYNQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCANHDFFVFWGQGTLVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIVVAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR 1472 Anti-BCMAMALPVTALLLPLALLLHAARPDIQMTQSPSSLSASLGDRVTITCRT CAR of CTX-SQDISNHLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY 177SLTISSLQPEDIGTYYCQQGNTLPPTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAELKKPGASVKISCKASGYTFTEYTINWVRQAPGQRLEWMGDIYPDNYSIRYNQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCANHDFFVFWGQGTLVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIVVAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQA LPPR 1473 Anti-BCMAMALPVTALLLPLALLLHAARPDIQMTQSPSSLSASVGDRVTITCQA CAR of CTX-SQDISNYLNWYQQKPGKAPKLLIYYTSRLETGVPSRFSGSGSGTDF 178TFTISSLQPEDIATYYCQQGNTLPPTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGPELKKPGASVKISCKTSGYTFTEYTINWVKQAPGQGLEWIGDIYPDNYNIRYNQKFQGKATITRDTSSSTAYMELSSLRSEDTAVYYCANHDFFVFWGQGTLVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPP R 1474 Anti-BCMAMALPVTALLLPLALLLHAARPDIQMTQSPSSLSASLGDRVTITCRT CAR of CTX-SQDISNHLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY 179SLTISSLQPEDIGTYYCQQGNTLPPTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGPELKKPGASVKISCKTSGYTFTEYTINWVKQAPGQGLEWIGDIYPDNYNIRYNQKFQGKATITRDTSSSTAYMELSSLRSEDTAVYYCANHDFFVFWGQGTLVTVSSSAAAFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPP R

TABLE 38 scFv Nucleotide Sequences SEQ ID NO: Description Sequence 1333Anti-CD19 ATTCAGATGACTCAGACCACCAGTAGCTTGTCTGCCTCACTGG scFv of CTX-GAGACCGAGTAACAATCTCCTGCAGGGCAAGTCAAGACATTAG 131 to CTX-CAAATACCTCAATTGGTACCAGCAGAAGCCCGACGGAACGGTA 141AAACTCCTCATCTATCATACGTCAAGGTTGCATTCCGGAGTACCGTCACGATTTTCAGGTTCTGGGAGCGGAACTGACTATTCCTTGACTATTTCAAACCTCGAGCAGGAGGACATTGCGACATATTTTTGTCAACAAGGTAATACCCTCCCTTACACTTTCGGAGGAGGAACCAAACTCGAAATTACCGGGTCCACCAGTGGCTCTGGGAAGCCTGGCAGTGGAGAAGGTTCCACTAAAGGCGAGGTGAAGCTCCAGGAGAGCGGCCCCGGTCTCGTTGCCCCCAGTCAAAGCCTCTCTGTAACGTGCACAGTGAGTGGTGTATCATTGCCTGATTATGGCGTCTCCTGGATAAGGCAGCCCCCGCGAAAGGGTCTTGAATGGCTTGGGGTAATATGGGGCTCAGAGACAACGTATTATAACTCCGCTCTCAAAAGTCGCTTGACGATAATAAAAGATAACTCCAAGAGTCAAGTTTTCCTTAAAATGAACAGTTTGCAGACTGACGATACCGCTATATATTATTGTGCTAAACATTATTACTACGGCGGTAGTTACGCGATGGATTATTGGGGGCAGGGGACTTCTGTCACAGTCAGT 1475 Anti-CD70AGATATAGTTATGACCCAATCACCCGATAGTCTTGCGGTAAGCC scFv of CTX-TGGGGGAGCGAGCAACAATAAACTGTCGGGCATCAAAATCCGT 142CAGTACAAGCGGGTATTCATTCATGCACTGGTATCAACAGAAACCCGGTCAGCCACCCAAGCTCCTGATTTATCTTGCGTCTAATCTTGAGTCCGGCGTCCCAGACCGGTTTTCCGGCTCCGGGAGCGGCACGGATTTTACTCTTACTATTTCTAGCCTTCAGGCCGAAGATGTGGCGGTATACTACTGCCAGCATTCAAGGGAAGTTCCTTGGACGTTCGGTCAGGGCACGAAAGTGGAAATTAAAGGCGGGGGGGGATCCGGCGGGGGAGGGTCTGGAGGAGGTGGCAGTGGTCAGGTCCAACTGGTGCAGTCCGGGGCAGAGGTAAAAAAACCCGGCGCGTCTGTTAAGGTTTCATGCAAGGCCAGTGGATATACTTTCACCAATTACGGAATGAACTGGGTGAGGCAGGCCCCTGGTCAAGGCCTGAAATGGATGGGATGGATAAACACGTACACCGGTGAACCTACCTATGCCGATGCCTTTAAGGGTCGGGTTACGATGACGAGAGACACCTCCATATCAACAGCCTACATGGAGCTCAGCAGATTGAGGAGTGACGATACGGCAGTCTATTACTGTGCAAGAGACTACGGCGATTATGGCATGGATTACTGGGGCCAGGGCACTACAGTAACCGTTTC CAGC 1476 Anti-CD70BCAGGTCCAGTTGGTGCAAAGCGGGGCGGAGGTGAAAAAACCC scFv of CTX-GGCGCTTCCGTGAAGGTGTCCTGTAAGGCGTCCGGTTATACGTT 145 and CTX-CACGAACTACGGGATGAATTGGGTTCGCCAAGCGCCGGGGCAG 145bGGACTGAAATGGATGGGGTGGATAAATACCTACACCGGCGAACCTACATACGCCGACGCTTTTAAAGGGCGAGTCACTATGACGCGCGATACCAGCATATCCACCGCATACATGGAGCTGTCCCGACTCCGGTCAGACGACACGGCTGTCTACTATTGTGCTCGGGACTATGGCGATTATGGCATGGACTACTGGGGTCAGGGTACGACTGTAACAGTTAGTAGTGGTGGAGGCGGCAGTGGCGGGGGGGGAAGCGGAGGAGGGGGTTCTGGTGACATAGTTATGACCCAATCCCCAGATAGTTTGGCGGTTTCTCTGGGCGAGAGGGCAACGATTAATTGTCGCGCATCAAAGAGCGTTTCAACGAGCGGATATTCTTTTATGCATTGGTACCAGCAAAAACCCGGACAACCGCCGAAGCTGCTGATCTACTTGGCTTCAAATCTTGAGTCTGGGGTGCCGGACCGATTTTCTGGTAGTGGAAGCGGAACTGACTTTACGCTCACGATCAGTTCACTGCAGGCTGAGGATGTAGCGGTCTATTATTGCCAGCACAGTAGAGAAGTCCCCTGGACCTTCGGTCAAGGCACGAAAGTAGAA ATTAAA 1477 Anti-BCMA-1CAGGTGCAGTTACAACAGTCAGGAGGAGGATTAGTGCAGCCA scFv of CTXGGAGGATCTCTGAAACTGTCTTGTGCCGCCAGCGGAATCGATT 152 and CTX-TTAGCAGGTACTGGATGTCTTGGGTGAGAAGAGCCCCTGGAAA 153AGGACTGGAGTGGATCGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGTCTTCTGGAGGAGGAGGATCCGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGAGATATTGTGATGACACAAAGCCAGCGGTTCATGACCACATCTGTGGGCGACAGAGTGAGCGTGACCTGTAAAGCTTCTCAGTCTGTGGACAGCAATGTTGCCTGGTATCAGCAGAAGCCCAGACAGAGCCCTAAAGCCCTGATCTTTTCTGCCAGCCTGAGATTTTCTGGCGTTCCTGCCAGATTTACCGGCTCTGGCTCTGGCACCGATTTTACACTGACCATCAGCAATCTGCAGTCTGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAACTACCCCCTGACCTTTGGAGCTGGCACAAAACTGGAGCTGAAG 1478 Anti-BCMA-2GACATCGTGATGACCCAAAGCCAGAGGTTCATGACCACATCTG scFv of CTX-TGGGCGATAGAGTGAGCGTGACCTGTAAAGCCTCTCAGTCTGT 154 and CTX-GGACAGCAATGTTGCCTGGTATCAGCAGAAGCCTAGACAGAGC 155CCTAAAGCCCTGATCTTTAGCGCCAGCCTGAGATTTAGCGGAGTTCCTGCCAGATTTACCGGAAGCGGATCTGGAACCGATTTTACACTGACCATCAGCAACCTGCAGAGCGAGGATCTGGCCGAGTACTTTTGCCAGCAGTACAACAATTACCCTCTGACCTTTGGAGCCGGCACAAAGCTGGAGCTGAAAGGAGGAGGAGGATCTGGTGGTGGTGGTTCAGGAGGTGGAGGTTCGGGACAAGTTCAATTACAGCAATCTGGAGGAGGACTGGTTCAGCCTGGAGGAAGCCTGAAGCTGTCTTGTGCCGCTTCTGGAATCGATTTTAGCAGATACTGGATGAGCTGGGTGAGAAGAGCCCCTGGCAAAGGACTGGAGTGGATTGGCGAGATTAATCCTGATAGCAGCACCATCAACTATGCCCCTAGCCTGAAGGACAAGTTCATCATCAGCCGGGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCAAGGTGAGGAGCGAGGATACAGCTCTGTACTACTGTGCCAGCCTGTACTACGATTACGGAGATGCTATGGACTATTGGGGCCAGGGAACAAGCGTTACAGTGAGCAGC 1479 Anti-BCMAGAGGTCCAGCTGGTGGAGAGCGGCGGAGGACTGGTCCAGCCT scFv of CTX-GGCGGCTCCCTGAAACTGAGCTGCGCCGCCAGCGGCATCGACT 160 and CTX-TCAGCAGGTACTGGATGAGCTGGGTGAGACAGGCCCCTGGCAA 160bGGGCCTGGAATGGATCGGCGAGATCAACCCCGACTCCAGCACCATCAACTACGCCGACAGCGTCAAGGGCAGGTTCACCATTAGCAGGGACAATGCCAAGAACACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAAGACACCGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCTCCGGAGGAGGCGGCAGCGGCGGAGGCGGCAGCGGCGGAGGCGGCAGCGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCTCCGTGGGAGATAGGGTGACAATCACCTGTAGGGCCAGCCAGAGCGTGGACTCCAACGTGGCCTGGTATCAACAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTTTCCGCCTCCCTGAGGTTCAGCGGAGTCCCCAGCAGGTTCTCCGGATCCGGCTCCGGAACCGACTTTACCCTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAGCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAG 1480 Anti-BCMAGAGGTGCAGCTGGTGGAGAGCGGAGGAGGACTGGTGCAGCCC scFv of CTX-GGAGGCTCCCTGAAGCTGAGCTGCGCTGCCTCCGGCATCGACT 161TCAGCAGGTACTGGATGAGCTGGGTGAGGCAGGCTCCCGGCAAAGGCCTGGAGTGGATCGGCGAGATCAACCCCGACAGCAGCACCATCAACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAATACCCTGTACCTGCAGATGAACCTGAGCAGGGCCGAGGACACAGCCCTGTACTACTGTGCCAGCCTGTACTACGACTATGGAGACGCTATGGACTACTGGGGCCAGGGAACCCTGGTGACCGTGAGCAGCGGAGGCGGAGGCTCCGGCGGCGGAGGCAGCGGAGGAGGCGGCAGCGATATCCAGATGACCCAGTCCCCCAGCTCCCTGAGCGCTAGCCCTGGCGACAGGGTGAGCGTGACATGCAAGGCCAGCCAGAGCGTGGACAGCAACGTGGCCTGGTACCAGCAGAAACCCAGACAGGCCCCCAAGGCCCTGATCTTCAGCGCCAGCCTGAGGTTTAGCGGCGTGCCCGCTAGGTTTACCGGATCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCAACCTGCAGTCCGAGGACTTCGCCACCTACTACTGCCAGCAGTACAACAACTACCCCCTGACATTCGGCGCCGGAACCAAGCTGGAGATCAAG 1481 Anti-BCMAGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCTAGCG scFv of CTX-TGGGCGACAGGGTGACCATCACCTGCAGGGCCAGCCAGAGCGT 162GGACTCCAACGTGGCCTGGTACCAGCAGAAGCCCGAGAAGGCCCCCAAGAGCCTGATCTTCAGCGCCAGCCTGAGGTTCTCCGGAGTGCCTAGCAGATTTAGCGGCAGCGGCAGCGGCACAGACTTCACCCTGACCATCAGCAGCCTCCAGCCCGAGGATTTCGCCACCTACTACTGCCAGCAGTACAACTCCTACCCCCTGACCTTCGGCGCCGGCACAAAGCTGGAGATCAAGGGAGGAGGAGGAAGCGGAGGAGGAGGAAGCGGAGGCGGAGGAAGCGAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGCAACCTGGAGGCAGCCTGAAGCTGAGCTGTGCCGCCAGCGGAATCGACTTCAGCAGGTACTGGATGTCCTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAGTGGATCGGAGAGATCAACCCCGACAGCTCCACCATCAACTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGAGACAACGCCAAGAACACCCTGTACCTGCAGATGAACCTGTCCAGAGCCGAGGACACCGCCCTGTACTACTGCGCCAGCCTGTATTACGACTACGGCGACGCTATGGACTACTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGC 1482 Anti-BCMAGACATCCAAATGACCCAGTCCCCTAGCAGCCTGTCCGCCAGCC scFv of CTX-CTGGAGACAGGGTGTCCGTGACCTGCAAGGCCAGCCAGTCCGT 163GGACAGCAACGTCGCCTGGTATCAGCAGAAGCCCAGGCAAGCTCCCAAGGCTCTGATCTTCTCCGCCAGCCTGAGATTTTCCGGCGTGCCCGCCAGATTCACCGGAAGCGGCAGCGGCACCGACTTCACCCTGACCATCAGCAACCTGCAGAGCGAGGATTTCGCCACATACTACTGCCAGCAGTACAACAACTACCCCCTGACCTTCGGAGCCGGCACCAAGCTGGAGATCAAAGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGATCCGAAGTGCAGCTGGTGGAAAGCGGAGGCGGACTCGTGCAGCCTGGCGGAAGCCTGAAGCTGAGCTGTGCCGCCAGCGGCATCGACTTCAGCAGGTACTGGATGAGCTGGGTGAGGCAGGCTCCCGGCAAAGGCCTGGAGTGGATCGGCGAGATCAACCCTGACAGCAGCACCATCAACTACGCCGACAGCGTGAAAGGCAGGTTCACCATCAGCAGGGACAACGCCAAGAACACCCTGTACCTGCAGATGAACCTGTCCAGAGCCGAGGACACCGCCCTGTACTACTGCGCCAGCCTGTACTACGACTACGGCGACGCTATGGACTACTGGGGCCAAGGCACCCTCGTGACCGTCAGCTCC 1483 Anti-BCMAGAGGTGCAGCTGCAGCAGTCCGGCCCTGAGCTCGTGAAGCCTG scFv of CTX-GAGCCAGCGTGAAAATGAGCTGTAAGGCCTCCGGCAACACCCT 164CACCAACTACGTGATCCATTGGATGAAGCAGATGCCCGGCCAGGGCCTGGACTGGATTGGCTACATTCTGCCCTACAACGACCTGACCAAGTACAACGAGAAGTTCACCGGCAAGGCCACCCTGACCAGCGATAAGAGCTCCAGCAGCGCCTACATGGAGCTGAACTCCCTGACCAGCGAGGACAGCGCCGTGTACTACTGCACCAGGTGGGACTGGGATGGCTTCTTCGACCCCTGGGGACAGGGCACCACCCTGACAGTGTCCAGCGGAGGAGGCGGCAGCGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGATATCGTGATGACACAGTCCCCTCTGAGCCTGCCTGTGAGCCTGGGCGACCAGGCCAGCATCAGCTGCAGGTCCACCCAGTCCCTGGTGCACTCCAACGGCAACACCCACCTGCACTGGTACCTGCAAAGGCCCGGCCAGTCCCCTAAGCTGCTGATCTACAGCGTGAGCAACAGGTTTAGCGAGGTGCCCGATAGATTTTCCGCCAGCGGCAGCGGCACCGACTTCACACTGAAGATCTCCAGGGTGGAGGCCGAGGATCTGGGCGTGTACTTCTGCAGCCAGACCAGCCACATCCCCTACACCTTCGGCGGCGGAACCAAGCTGGAGA TCAAG 1484 Anti-BCMAGACATCGTGATGACCCAGAGCCCCCTGAGCCTGCCTGTGTCCC scFv of CTX-TGGGAGACCAGGCTTCCATCAGCTGCAGGTCCACCCAGAGCCT 165GGTGCACTCCAACGGCAACACCCACCTGCACTGGTACCTGCAGAGGCCTGGCCAGTCCCCCAAGCTGCTGATCTACAGCGTGAGCAATAGGTTCAGCGAGGTGCCCGACAGATTCAGCGCCAGCGGAAGCGGCACCGACTTCACCCTGAAGATCAGCAGGGTCGAGGCCGAAGATCTGGGCGTGTACTTCTGCTCCCAGACATCCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGGAGATTAAGGGCGGCGGAGGATCCGGCGGAGGAGGATCCGGAGGAGGAGGAAGCGAGGTGCAGCTGCAGCAGAGCGGACCCGAGCTGGTGAAACCCGGAGCCAGCGTCAAAATGAGCTGCAAGGCCAGCGGCAACACCCTGACCAACTACGTCATCCACTGGATGAAGCAGATGCCCGGACAGGGCCTGGACTGGATCGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAACGAGAAATTCACCGGCAAGGCCACCCTGACCAGCGACAAGAGCAGCAGCAGCGCCTACATGGAGCTGAACAGCCTGACCAGCGAGGACTCCGCCGTGTACTATTGCACCAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACACTCACCGT GAGCTCC 1485 Anti-BCMACAGGTGCAGCTGGTGCAGAGCGGAGCCGAGCTCAAGAAGCCC scFv of CTX-GGAGCCTCCGTGAAGGTGAGCTGCAAGGCCAGCGGCAACACC 166 and CTX-CTGACCAACTACGTGATCCACTGGGTGAGACAAGCCCCCGGCC 166bAAAGGCTGGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCTCCACCGCCTATATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGTACAAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGCACAACAGTGACCGTCAGCAGCGGCGGCGGAGGCAGCGGCGGCGGCGGCAGCGGCGGAGGCGGAAGCGAAATCGTGATGACCCAGAGCCCCGCCACACTGAGCGTGAGCCCTGGCGAGAGGGCCAGCATCTCCTGCAGGGCTAGCCAAAGCCTGGTGCACAGCAACGGCAACACCCACCTGCACTGGTACCAGCAGAGACCCGGACAGGCTCCCAGGCTGCTGATCTACAGCGTGAGCAACAGGTTCTCCGAGGTGCCTGCCAGGTTTAGCGGCAGCGGAAGCGGCACCGACTTTACCCTGACCATCAGCAGCGTGGAGTCCGAGGACTTCGCCGTGTATTACTGCAGCCAGACCAGCCACATCCCTTACACCTTCGGCGGCGGCACCAAGCTGG AGATCAAA 1486 Anti-BCMACAGGTGCAGCTGGTGCAGAGCGGCGCCGAGCTGAAGAAACCT scFv of CTX-GGCGCCAGCGTCAAGGTGAGCTGCAAGGCTTCCGGAAACACCC 167TCACCAACTACGTGATCCACTGGGTGAGGCAGGCCCCCGGACAGAGACTGGAGTGGATGGGCTACATTCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTCACCATCACCAGGGACAAGAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGTCCGAGGACACAGCCGTGTACTACTGCACCAGGTGGGACTGGGACGGATTCTTCGACCCTTGGGGCCAAGGCACCACAGTGACAGTGAGCTCCGGCGGAGGCGGCAGCGGCGGCGGAGGAAGCGGCGGCGGCGGAAGCGACATCGTGATGACCCAGAGCCCTCTGAGCCTGCCCGTGACACTGGGACAGCCTGCCACACTGTCCTGCAGGAGCACCCAGAGCCTGGTGCATAGCAACGGCAACACCCACCTGCACTGGTTCCAGCAGAGACCTGGCCAGAGCCCCCTGAGACTGATCTACAGCGTGAGCAACAGGGACAGCGGCGTGCCCGATAGATTTAGCGGCAGCGGCAGCGGCACCGACTTTACCCTGAAAATCTCCAGGGTGGAGGCCGAGGATGTGGGCGTGTATTACTGCTCCCAGACAAGCCACATTCCCTATACATTCGGCGGCGGCACCAAGCTGGA GATCAAG 1487 Anti-BCMAGAAATCGTGATGACCCAGAGCCCTGCCACACTGAGCGTGAGCC scFv of CTX-CTGGCGAGAGAGCCAGCATCAGCTGCAGGGCCTCCCAGAGCCT 168GGTGCACTCCAACGGCAATACCCACCTGCACTGGTATCAGCAGAGACCCGGCCAGGCCCCTAGGCTGCTGATCTACTCCGTGAGCAACAGGTTCTCCGAGGTGCCCGCCAGATTCAGCGGATCCGGCAGCGGCACCGACTTCACCCTCACCATCTCCAGCGTGGAGAGCGAGGACTTCGCCGTCTACTACTGCAGCCAGACAAGCCACATCCCCTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGGGCGGCGGCGGCAGCGGCGGCGGAGGCAGCGGAGGCGGCGGATCCCAGGTGCAACTGGTGCAGAGCGGAGCCGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGGTCAGCTGCAAGGCCAGCGGCAACACCCTGACAAACTACGTGATCCACTGGGTGAGGCAGGCCCCTGGCCAAAGGCTCGAGTGGATGGGCTACATCCTCCCCTACAACGACCTGACCAAGTACTCCCAGAAGTTCCAGGGCAGGGTGACCATCACCAGGGATAAGAGCGCCAGCACCGCCTACATGGAACTCAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCACCAGGTGGGACTGGGATGGCTTCTTCGACCCTTGGGGCCAGGGCACCACCGTGACAGT GAGCTCC 1488 Anti-BCMAGACATCGTGATGACACAATCCCCCCTCAGCCTGCCTGTGACAC scFv of CTX-TGGGCCAGCCTGCCACCCTGAGCTGCAGGAGCACCCAGTCCCT 169GGTGCACTCCAACGGCAACACCCACCTGCACTGGTTCCAGCAGAGGCCTGGACAGAGCCCCCTGAGGCTGATCTACAGCGTGAGCAACAGGGACTCCGGCGTGCCCGATAGATTCAGCGGCAGCGGCTCCGGCACCGATTTCACCCTGAAGATCTCCAGAGTGGAAGCCGAGGACGTGGGCGTCTACTACTGCAGCCAGACCAGCCATATCCCCTACACCTTCGGCGGCGGCACCAAGCTGGAGATCAAGGGAGGCGGCGGAAGCGGCGGAGGCGGATCCGGAGGCGGAGGCTCCCAAGTGCAGCTGGTGCAGAGCGGCGCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAGGTGAGCTGCAAGGCCAGCGGAAACACCCTGACCAACTACGTGATCCACTGGGTGAGACAGGCCCCCGGACAGAGACTCGAGTGGATGGGCTACATCCTGCCCTACAACGACCTGACCAAGTACAGCCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGACAAGAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTGTACTACTGCACCAGGTGGGACTGGGACGGCTTCTTTGACCCCTGGGGCCAGGGAACCACAGTGAC CGTGTCCTCC 1489 Anti-BCMAGAGGTGCAGCTGCAGCAGAGCGGCCCTGAGCTGGTGAAGCCC scFv of CTX-GGCGCCAGCGTGAAGATCAGCTGCAAGACCTCCGGCTATACCT 170TTACCGAGTACACCATCAACTGGGTGAAGCAGAGCCACGGCAAGAGCCTGGAGTGGATCGGCGATATCTACCCCGACAACTACAACATCAGGTACAACCAGAAGTTCAAGGGCAAGGCCACCCTGACCGTGGACAAGTCCAGCAGCACCGCCTACATGGAGCTGAGGAGCCTGTCCAGCGAGGACTCCGCCATCTACTACTGCGCCAACCACGACTTTTTCGTCTTCTGGGGACAGGGCACCCTGGTGACAGTGTCCGCTGGCGGCGGCGGCAGCGGCGGCGGCGGCTCCGGAGGCGGCGGCAGCGACATCCAGATGACACAGGCCACAAGCTCCCTGTCCGCCAGCCTGGGCGATAGGGTGACCATCAATTGCAGGACCTCCCAGGACATCAGCAACCACCTGAACTGGTACCAGCAGAAACCCGACGGCACCGTGAAGCTGCTCATCTACTACACCAGCAGGCTGCAGTCCGGCGTCCCTAGCAGATTCAGCGGATCCGGCAGCGGCACCGACTATAGCCTGACCATCAGCAACCTCGAGCAGGAGGACATCGGCACCTACTTCTGCCATCAGGGCAACACCCTGCCCCCTACCTTTGGCG GCGGCACAAAGCTGGAGATTAAG1490 Anti-BCMA GATATCCAGATGACCCAGGCCACCAGCAGCCTGAGCGCTTCCC scFv of CTX-TCGGCGACAGGGTGACCATCAACTGCAGGACCAGCCAGGACAT 171CTCCAACCACCTGAACTGGTACCAGCAGAAGCCCGACGGCACCGTGAAACTGCTGATCTACTACACCAGCAGACTGCAGAGCGGCGTGCCCTCCAGATTTTCCGGCAGCGGCTCCGGCACCGACTACAGCCTGACCATTAGCAACCTGGAGCAGGAGGACATCGGAACCTACTTCTGCCACCAGGGCAACACACTGCCTCCCACCTTCGGCGGCGGCACAAAGCTCGAGATCAAGGGCGGCGGCGGAAGCGGCGGCGGCGGCAGCGGCGGCGGAGGCTCCGAGGTGCAACTGCAACAGAGCGGACCTGAGCTGGTGAAGCCTGGCGCCAGCGTGAAGATCTCCTGTAAGACCAGCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAAGCAGAGCCACGGCAAGAGCCTCGAATGGATCGGCGACATCTATCCCGACAACTACAATATCAGATACAACCAGAAGTTCAAGGGAAAGGCCACCCTGACCGTGGATAAGTCCTCCTCCACCGCTTACATGGAGCTGAGGAGCCTGAGCAGCGAGGACTCCGCCATCTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCA AGGCACCCTCGTGACCGTGAGCGCC1491 Anti-BCMA CAGGTGCAGCTGGTGCAGTCCGGCGCTGAGCTGAAGAAGCCCG scFv of CTX-GCGCCAGCGTGAAGATCAGCTGCAAGGCCAGCGGCTACACCTT 172CACCGAATACACCATCAACTGGGTGAGACAGGCCCCTGGACAGAGGCTCGAGTGGATGGGCGACATCTACCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGACACCAGCGCCAGCACCGCCTATATGGAGCTGAGCAGCCTGAGATCCGAGGACACCGCCGTCTATTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACACTGGTGACCGTGTCCAGCGGCGGCGGCGGCAGCGGCGGCGGAGGAAGCGGCGGCGGCGGCAGCGATATCCAGATGACCCAGAGCCCCTCCTCCCTGAGCGCTAGCGTGGGCGACAGGGTGACCATTACCTGTCAGGCCTCCCAGGACATCAGCAACTACCTGAACTGGTACCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTATTACACCAGCAGGCTGGAGACCGGCGTGCCCTCCAGATTCAGCGGCTCCGGCTCCGGAACCGACTTCACCTTCACCATCAGCTCCCTGCAGCCTGAGGACATCGCCACCTACTACTGCCAGCAGGGCAACACCCTGCCTCCCACATTCGGCG GCGGCACAAAGGTGGAGATCAAA 1492Anti-BCMA CAGGTGCAGCTGGTCCAGTCCGGCGCCGAACTGAAGAAGCCTG scFv of CTX-GCGCCAGCGTGAAGATCAGCTGCAAGGCCTCCGGCTACACCTT 173CACCGAGTACACCATCAACTGGGTGAGGCAAGCCCCCGGCCAGAGACTGGAGTGGATGGGCGACATCTACCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGGGATACCAGCGCCAGCACAGCCTATATGGAGCTGTCCTCCCTGAGATCCGAGGACACCGCCGTGTATTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAAGGCACCCTGGTGACCGTGAGCAGCGGCGGCGGCGGCTCCGGCGGCGGAGGCTCCGGAGGCGGAGGCAGCGACATCCAGATGACCCAGAGCCCTTCCAGCCTGAGCGCTAGCCTGGGCGACAGGGTGACCATCACCTGCAGGACCAGCCAGGACATCAGCAATCACCTGAACTGGTACCAGCAAAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCAGCAGGCTGGAAAGCGGCGTGCCTAGCAGGTTCAGCGGCAGCGGCTCCGGAACCGACTACAGCCTGACCATTAGCAGCCTGCAACCTGAGGACATCGGCACCTATTACTGCCAGCAGGGCAACACCCTGCCTCCTACCTTTGGC GGCGGCACCAAACTCGAGATCAAG1493 Anti-BCMA CAGGTGCAGCTGGTGCAGAGCGGCCCTGAGCTGAAGAAGCCC scFv of CTX-GGAGCCAGCGTGAAGATCTCCTGCAAGACCTCCGGCTACACCT 174TCACCGAGTACACCATCAACTGGGTGAAGCAGGCCCCCGGACAGGGACTGGAATGGATCGGCGACATCTACCCCGACAACTACAACATCAGGTACAACCAGAAGTTCCAAGGCAAGGCCACCATCACAAGGGACACCAGCAGCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGATACCGCCGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCGGAGGAGGCGGAAGCGGAGGAGGAGGATCCGGAGGAGGAGGCAGCGACATCCAGATGACCCAGTCCCCCTCCTCCCTGAGCGCCTCCGTGGGAGACAGGGTGACCATCACCTGCCAGGCCAGCCAGGACATCAGCAACTACCTGAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATTTACTACACCAGCAGGCTGGAAACCGGCGTGCCCAGCAGATTTAGCGGCAGCGGCAGCGGCACCGACTTTACCTTTACCATCTCCAGCCTGCAGCCCGAGGATATCGCCACATACTACTGCCAGCAGGGCAACACCCTCCCCCCTACCTTTGGC GGCGGCACCAAGGTGGAGATTAAG1494 Anti-BCMA CAGGTGCAGCTGGTGCAGTCCGGCCCCGAACTGAAAAAGCCCG scFv of CTX-GCGCCAGCGTCAAGATCAGCTGCAAGACCTCCGGCTACACCTT 175CACCGAGTACACCATCAACTGGGTGAAGCAGGCCCCCGGCCAGGGACTGGAATGGATTGGCGACATCTACCCCGACAACTACAACATTAGGTATAACCAGAAGTTCCAGGGCAAGGCCACCATCACAAGAGACACCAGCAGCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACAGTGTCCAGCGGCGGCGGCGGCTCCGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGACATTCAGATGACACAGAGCCCCTCCAGCCTGAGCGCCAGCCTGGGCGATAGGGTGACCATCACCTGCAGAACCAGCCAGGACATCAGCAACCACCTGAATTGGTACCAGCAGAAGCCCGGAAAGGCCCCCAAACTGCTGATCTACTACACCAGCAGGCTGGAGAGCGGCGTGCCTAGCAGGTTTAGCGGCAGCGGCAGCGGCACAGATTACAGCCTGACCATCAGCAGCCTGCAGCCCGAAGACATCGGCACCTACTACTGCCAGCAGGGCAACACCCTGCCCCCTACCTTTGGC GGAGGCACCAAGCTGGAGATCAAG1495 Anti-BCMA GACATCCAGATGACACAGAGCCCTAGCAGCCTGAGCGCTTCCG scFv of CTX-TGGGCGACAGGGTGACCATCACCTGCCAGGCCAGCCAGGACAT 176CAGCAACTACCTCAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCTCCAGGCTGGAGACCGGAGTGCCCTCCAGATTTTCCGGCAGCGGCAGCGGCACCGATTTCACCTTCACCATCAGCAGCCTGCAGCCCGAGGACATCGCCACCTACTATTGCCAGCAGGGCAACACCCTGCCCCCCACATTTGGAGGCGGCACCAAGGTGGAGATCAAGGGCGGAGGAGGAAGCGGAGGAGGAGGAAGCGGAGGAGGCGGAAGCCAGGTGCAGCTGGTGCAGAGCGGCGCTGAGCTCAAGAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAAGCCTCCGGATACACCTTCACCGAGTACACCATCAATTGGGTGAGACAGGCCCCCGGCCAAAGACTGGAGTGGATGGGCGACATCTATCCCGACAACTACAGCATCAGGTACAACCAGAAGTTCCAGGGCAGGGTGACAATCACCAGAGACACCAGCGCCAGCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTACTGCGCCAATCACGACTTCTTCGTGTTCTGGGGCCAGGGAACCCTGGTGACCGTCAGCTCC 1496 Anti-BCMAGATATCCAGATGACACAGAGCCCTAGCTCCCTGAGCGCCAGCC scFv of CTX-TGGGCGATAGGGTGACCATCACCTGCAGGACCTCCCAGGACAT 177CAGCAACCACCTGAACTGGTACCAGCAGAAGCCCGGCAAAGCCCCCAAGCTGCTGATCTACTACACCAGCAGGCTGGAAAGCGGCGTGCCCAGCAGGTTTAGCGGAAGCGGCAGCGGCACCGACTACAGCCTGACCATCAGCTCCCTGCAGCCCGAGGACATCGGCACCTACTACTGCCAGCAGGGCAACACCCTGCCTCCCACCTTCGGAGGCGGAACCAAGCTGGAGATTAAGGGAGGCGGCGGAAGCGGCGGCGGCGGCTCCGGCGGAGGAGGCAGCCAGGTGCAGCTGGTGCAGTCCGGAGCCGAGCTGAAAAAGCCTGGCGCCAGCGTGAAGATCAGCTGCAAGGCCAGCGGCTACACCTTCACCGAGTACACCATCAACTGGGTGAGGCAGGCCCCTGGCCAGAGACTCGAGTGGATGGGCGACATCTACCCCGACAACTACTCCATCAGGTACAACCAGAAGTTTCAGGGCAGGGTGACCATTACCAGGGACACCAGCGCCAGCACAGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGATACAGCCGTCTACTACTGCGCCAACCACGACTTTTTCGTGTTCTGGGGACAGGGCACCCTGGTGACCGTGTCCTCC 1497 Anti-BCMAGACATCCAAATGACCCAGAGCCCTAGCTCCCTGAGCGCTTCCG scFv of CTX-TGGGCGACAGAGTGACCATTACCTGCCAGGCCAGCCAGGACAT 178CAGCAACTACCTGAACTGGTATCAGCAGAAGCCTGGCAAGGCCCCCAAGCTGCTGATCTACTACACCAGCAGGCTGGAGACCGGAGTGCCCAGCAGGTTTAGCGGCTCCGGATCCGGCACCGACTTCACCTTCACCATCTCCAGCCTGCAGCCCGAGGACATCGCCACCTACTACTGCCAGCAGGGCAATACCCTCCCCCCTACCTTCGGAGGCGGCACCAAGGTGGAGATCAAGGGCGGCGGCGGCTCCGGCGGCGGCGGCAGCGGCGGAGGCGGCAGCCAGGTGCAACTGGTGCAGAGCGGCCCTGAGCTGAAGAAACCCGGCGCCAGCGTGAAAATCAGCTGCAAGACCAGCGGCTACACATTCACCGAGTACACCATCAACTGGGTGAAGCAGGCTCCCGGACAGGGACTGGAGTGGATCGGCGACATCTACCCTGACAACTACAACATCAGATACAACCAAAAGTTCCAGGGCAAGGCCACCATCACCAGGGACACCAGCTCCTCCACCGCCTACATGGAGCTGAGCAGCCTGAGGAGCGAGGACACCGCTGTGTACTACTGCGCCAACCACGACTTCTTCGTGTTCTGGGGCCA GGGAACCCTGGTGACCGTGAGCAGC1498 Anti-BCMA GATATCCAGATGACACAAAGCCCCAGCAGCCTGTCCGCTAGCC scFv of CTX-TGGGCGATAGGGTGACCATCACATGCAGGACCAGCCAGGACAT 179CTCCAACCACCTGAACTGGTACCAGCAGAAGCCTGGAAAGGCCCCCAAACTGCTGATCTACTACACCAGCAGGCTGGAGAGCGGCGTGCCTAGCAGGTTTTCCGGCAGCGGCAGCGGCACCGACTATAGCCTGACCATCAGCTCCCTGCAGCCCGAGGACATCGGCACCTACTACTGCCAGCAGGGAAACACACTGCCCCCCACCTTTGGCGGCGGCACAAAGCTGGAGATCAAGGGCGGCGGCGGATCCGGCGGCGGAGGCAGCGGAGGAGGAGGAAGCCAGGTGCAGCTGGTGCAGTCCGGCCCTGAGCTGAAGAAGCCCGGAGCCAGCGTGAAAATTAGCTGCAAGACCTCCGGCTACACATTCACCGAGTACACCATCAACTGGGTGAAGCAGGCTCCCGGCCAGGGACTGGAGTGGATCGGCGACATCTACCCCGACAACTACAACATCAGGTACAACCAGAAATTCCAGGGCAAGGCCACCATCACCAGGGACACCAGCTCCTCCACCGCCTATATGGAGCTGTCCAGCCTGAGAAGCGAGGATACCGCCGTGTACTACTGCGCCAACCACGATTTCTTCGTGTTCTGGGGCCA GGGCACACTGGTCACCGTGAGCAGC

TABLE 39 scFv Amino Acid Sequences SEQ ID NO: Description Sequence 1334Anti-CD19 IQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKL scFv of CTX-LIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNT 131 to CTX-LPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAP 141SQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGS YAMDYWGQGTSVTVS 1499Anti-CD70A DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSFMHWYQQKPG scFv of CTX-QPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 142CQHSREVPWTFGQGTKVEIKGGGGSGGGGSGGGGSGQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLKWMGWINTYTGEPTYADAFKGRVTMTRDTSISTAYMELSRLRSDDTAVYY CARDYGDYGMDYWGQGTTVTVSS1500 Anti-CD70B QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQ scFv of CTX-GLKWMGWINTYTGEPTYADAFKGRVTMTRDTSISTAYMELSRLR 145 and CTX-SDDTAVYYCARDYGDYGMDYWGQGTTVTVSSGGGGSGGGGSG 145bGGGSGDIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDV AVYYCQHSREVPWTFGQGTKVEIK1501 Anti-BCMA-1 QVQLQQSGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRRAPGK scFv of CTXGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNTLYLQMSKVRSED 152 and CTX-TALYYCASLYYDYGDAMDYWGQGTSVTVSSGGGGSGGGGSGG 153GGSGDIVMTQSQRFMTTSVGDRVSVTCKASQSVDSNVAWYQQKPRQSPKALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDLAEY FCQQYNNYPLTFGAGTKLELK1502 Anti-BCMA-2 DIVMTQSQRFMTTSVGDRVSVTCKASQSVDSNVAWYQQKPRQSPscFv of CTX- KALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDLAEYFCQQY154 and CTX- NNYPLTFGAGTKLELKGGGGSGGGGSGGGGSGQVQLQQSGGGL 155VQPGGSLKLSCAASGIDFSRYWMSWVRRAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNTLYLQMSKVRSEDTALYYCASLYY DYGDAMDYWGQGTSVTVSS 1503Anti-BCMA EVQLVESGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRQAPGKG scFv of CTX-LEWIGEINPDSSTINYADSVKGRFTISRDNAKNTLYLQMNLSRAED 160 and CTX-TALYYCASLYYDYGDAMDYWGQGTLVTVSSGGGGSGGGGSGG 160b (BCMA-GGSDIQMTQSPSSLSASVGDRVTITCRASQSVDSNVAWYQQKPEK 3)APKSLIFSASLRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YNSYPLTFGAGTKLEIK 1504Anti-BCMA EVQLVESGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRQAPGKG scFv of CTX-LEWIGEINPDSSTINYADSVKGRFTISRDNAKNTLYLQMNLSRAED 161 (BCMA-4)TALYYCASLYYDYGDAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASPGDRVSVTCKASQSVDSNVAWYQQKPRQAPKALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDFATYYC QQYNNYPLTFGAGTKLEIK 1505Anti-BCMA DIQMTQSPSSLSASVGDRVTITCRASQSVDSNVAWYQQKPEKAPK scFv of CTX-SLIFSASLRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNS 162 (BCMA-5)YPLTFGAGTKLEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYADSVKGRFTISRDNAKNTLYLQMNLSRAEDTALYYCASLYYDYG DAMDYWGQGTLVTVSS 1506Anti-BCMA DIQMTQSPSSLSASPGDRVSVTCKASQSVDSNVAWYQQKPRQAP scFv of CTX-KALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDFATYYCQQY 163 (BCMA-6)NNYPLTFGAGTKLEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYADSVKGRFTISRDNAKNTLYLQMNLSRAEDTALYYCASLYYD YGDAMDYWGQGTLVTVSS 1507Anti-BCMA EVQLQQSGPELVKPGASVKMSCKASGNTLTNYVIHWMKQMPGQ scFv of CTX-GLDWIGYILPYNDLTKYNEKFTGKATLTSDKSSSSAYMELNSLTSE 164 (BCMA-7)DSAVYYCTRWDWDGFFDPWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQSPLSLPVSLGDQASISCRSTQSLVHSNGNTHLHWYLQRPGQSPKLLIYSVSNRFSEVPDRFSASGSGTDFTLKISRVEAEDLGVYF CSQTSHIPYTFGGGTKLEIK1508 Anti-BCMA DIVMTQSPLSLPVSLGDQASISCRSTQSLVHSNGNTHLHWYLQRPscFv of CTX- GQSPKLLIYSVSNRFSEVPDRFSASGSGTDFTLKISRVEAEDLGVYF165 (BCMA-8) CSQTSHIPYTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLQQSGPELVKPGASVKMSCKASGNTLTNYVIHWMKQMPGQGLDWIGYILPYNDLTKYNEKFTGKATLTSDKSSSSAYMELNSLTSEDSAVYYCTR WDWDGFFDPWGQGTTLTVSS 1509Anti-BCMA QVQLVQSGAELKKPGASVKVSCKASGNTLTNYVIHWVRQAPGQR scFv of CTX-LEWMGYILPYNDLTKYSQKFQGRVTITRDKSASTAYMELSSLRSE 166 (BCMA-DTAVYYCTRWDWDGFFDPWGQGTTVTVSSGGGGSGGGGSGGG 11) and CTX-GSEIVMTQSPATLSVSPGERASISCRASQSLVHSNGNTHLHWYQQ 166bRPGQAPRLLIYSVSNRFSEVPARFSGSGSGTDFTLTISSVESEDFAV YYCSQTSHIPYTFGGGTKLEIK1510 Anti-BCMA QVQLVQSGAELKKPGASVKVSCKASGNTLTNYVIHWVRQAPGQR scFv of CTX-LEWMGYILPYNDLTKYSQKFQGRVTITRDKSASTAYMELSSLRSE 167 (BCMA-DTAVYYCTRWDWDGFFDPWGQGTTVTVSSGGGGSGGGGSGGG 12)GSDIVMTQSPLSLPVTLGQPATLSCRSTQSLVHSNGNTHLHWFQQRPGQSPLRLIYSVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCSQTSHIPYTFGGGTKLEIK1511 Anti-BCMA EIVMTQSPATLSVSPGERASISCRASQSLVHSNGNTHLHWYQQRPscFv of CTX- GQAPRLLIYSVSNRFSEVPARFSGSGSGTDFTLTISSVESEDFAVYY 168 (BCMA-CSQTSHIPYTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAE 13)LKKPGASVKVSCKASGNTLTNYVIHWVRQAPGQRLEWMGYILPYNDLTKYSQKFQGRVTITRDKSASTAYMELSSLRSEDTAVYYCTR WDWDGFFDPWGQGTTVTVSS 1512Anti-BCMA DIVMTQSPLSLPVTLGQPATLSCRSTQSLVHSNGNTHLHWFQQRP scFv of CTX-GQSPLRLIYSVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVY 169 (BCMA-14)YCSQTSHIPYTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAELKKPGASVKVSCKASGNTLTNYVIHWVRQAPGQRLEWMGYILPYNDLTKYSQKFQGRVTITRDKSASTAYMELSSLRSEDTAVYYCTR WDWDGFFDPWGQGTTVTVSS 1513Anti-BCMA EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTINWVKQSHGKSL scFv of CTX-EWIGDIYPDNYNIRYNQKFKGKATLTVDKSSSTAYMELRSLSSED 170 (BCMA-9)SAIYYCANHDFFVFWGQGTLVTVSAGGGGSGGGGSGGGGSDIQMTQATSSLSASLGDRVTINCRTSQDISNHLNWYQQKPDGTVKLLIYYTSRLQSGVPSRFSGSGSGTDYSLTISNLEQEDIGTYFCHQGNTLPP TFGGGTKLEIK 1514Anti-BCMA DIQMTQATSSLSASLGDRVTINCRTSQDISNHLNWYQQKPDGTVK scFv of CTX-LLIYYTSRLQSGVPSRFSGSGSGTDYSLTISNLEQEDIGTYFCHQGN 171 (BCMA-TLPPTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLQQSGPELVKPG 10)ASVKISCKTSGYTFFEYTINWVKQSHGKSLEWIGDIYPDNYNIRYNQKFKGKATLTVDKSSSTAYMELRSLSSEDSAIYYCANHDFFVFWG QGTLVTVSA 1515 Anti-BCMAQVQLVQSGAELKKPGASVKISCKASGYTFTEYTINWVRQAPGQRL scFv of CTX-EWMGDIYPDNYSIRYNQKFQGRVTITRDTSASTAYMELSSLRSED 172 (BCMA-TAVYYCANHDFFVFWGQGTLVTVSSGGGGSGGGGSGGGGSDIQ 15)MTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYYTSRLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLP PTFGGGTKVEIK 1516Anti-BCMA QVQLVQSGAELKKPGASVKISCKASGYTFTEYTINWVRQAPGQRL scFv of CTX-EWMGDIYPDNYSIRYNQKFQGRVTITRDTSASTAYMELSSLRSED 173 (BCMA-TAVYYCANHDFFVFWGQGTLVTVSSGGGGSGGGGSGGGGSDIQ 16)MTQSPSSLSASLGDRVTITCRTSQDISNHLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYSLTISSLQPEDIGTYYCQQGNTLPP TFGGGTKLEIK 1517Anti-BCMA QVQLVQSGPELKKPGASVKISCKTSGYTFILYTINWVKQAPGQGL scFv of CTX-EWIGDIYPDNYNIRYNQKFQGKATITRDTSSSTAYMELSSLRSEDT 174 (BCMA-AVYYCANHDFFVFWGQGTLVTVSSGGGGSGGGGSGGGGSDIQM 17)TQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYYTSRLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPPTF GGGTKVEIK 1518Anti-BCMA QVQLVQSGPELKKPGASVKISCKTSGYTFILYTINWVKQAPGQGL scFv of CTX-EWIGDIYPDNYNIRYNQKFQGKATITRDTSSSTAYMELSSLRSEDT 175 (BCMA-AVYYCANHDFFVFWGQGTLVTVSSGGGGSGGGGSGGGGSDIQM 18)TQSPSSLSASLGDRVTITCRTSQDISNHLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYSLTISSLQPEDIGTYYCQQGNTLPPT FGGGTKLEIK 1519Anti-BCMA DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPK scFv of CTX-LLIYYTSRLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGN 176 (BCMA-TLPPTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAELKKP 19)GASVKISCKASGYTFTEYTINWVRQAPGQRLEWMGDIYPDNYSIRYNQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCANHDFFVF WGQGTLVTVSS 1520 Anti-BCMADIQMTQSPSSLSASLGDRVTITCRTSQDISNHLNWYQQKPGKAPKL scFv of CTX-LIYYTSRLESGVPSRFSGSGSGTDYSLTISSLQPEDIGTYYCQQGNT 177 (BCMA-LPPTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAELKKPG 20)ASVKISCKASGYTFTEYTINWVRQAPGQRLEWMGDIYPDNYSIRYNQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCANHDFFVFW GQGTLVTVSS 1521 Anti-BCMADIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPK scFv of CTX-LLIYYTSRLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGN 178 (BCMA-TLPPTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGPELKKPG 21)ASVKISCKTSGYTFFEYTINWVKQAPGQGLEWIGDIYPDNYNIRYNQKFQGKATITRDTSSSTAYMELSSLRSEDTAVYYCANHDFFVFW GQGTLVTVSS 1522 Anti-BCMADIQMTQSPSSLSASLGDRVTITCRTSQDISNHLNWYQQKPGKAPKL scFv of CTX-LIYYTSRLESGVPSRFSGSGSGTDYSLTISSLQPEDIGTYYCQQGNT 179 (BCMA-LPPTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGPELKKPGA 22)SVKISCKTSGYTFTEYTINWVKQAPGQGLEWIGDIYPDNYNIRYNQKFQGKATITRDTSSSTAYMELSSLRSEDTAVYYCANHDFFVFWG QGTLVTVSS 1523 BCMA_VH1QVQLQQSGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRRAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNTLYLQMSKVRSEDTALYYCASLYYDYGDAMDYWGQGTSVTVSS 1524 BCMA_VH1. 1EVQLVESGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRQAPGKG (of CTX-160)LEWIGEINPDSSTINYADSVKGRFTISRDNAKNTLYLQMNLSRAEDTALYYCASLYYDYGDAMDYWGQGTLVTVSS 1525 BCMA_VL1DIVMTQSQRFMTTSVGDRVSVTCKASQSVDSNVAWYQQKPRQSPKALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDLAEYFCQQY NNYPLTFGAGTKLELK 1526BCMA_VL1.1 DIQMTQSPSSLSASVGDRVTITCRASQSVDSNVAWYQQKPEKAPK (of CTX-160)SLIFSASLRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNS YPLTFGAGTKLEIK 1527BCMA_VL1.2 DIQMTQSPSSLSASPGDRVSVTCKASQSVDSNVAWYQQKPRQAPKALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDFATYYCQQY NNYPLTFGAGTKLEIK 1528BCMA_VH2 EVQLQQSGPELVKPGASVKMSCKASGNTLTNYVIHWMKQMPGQGLDWIGYILPYNDLTKYNEKFTGKATLTSDKSSSSAYMELNSLTSEDSAVYYCTRWDWDGFFDPWGQGTTLTVSS 1529 BCMA_VL2DIVMTQSPLSLPVSLGDQASISCRSTQSLVHSNGNTHLHWYLQRPGQSPKLLIYSVSNRFSEVPDRFSASGSGTDFTLKISRVEAEDLGVYF CSQTSHIPYTFGGGTKLEIK1530 BCMA_VH3 EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTINWVKQSHGKSLEWIGDIYPDNYNIRYNQKFKGKATLTVDKSSSTAYMELRSLSSED SAIYYCANHDFFVFWGQGTLVTVSA1531 BCMA_VL3 DIQMTQATSSLSASLGDRVTINCRTSQDISNHLNWYQQKPDGTVKLLIYYTSRLQSGVPSRFSGSGSGTDYSLTISNLEQEDIGTYFCHQGN TLPPTFGGGTKLEIK 1589BCMA VH (of QVQLVQSGAELKKPGASVKVSCKASGNTLTNYVIHWVRQAPGQR CTX-166)LEWMGYILPYNDLTKYSQKFQGRVTITRDKSASTAYMELSSLRSEDTAVYYCTRWDWDGFFDPWGQGTTVTVSS 1590 BCMA VL (ofEIVMTQSPATLSVSPGERASISCRASQSLVHSNGNTHLHWYQQRP CTX-166)GQAPRLLIYSVSNRFSEVPARFSGSGSGTDFTLTISSVESEDFAVYY CSQTSHIPYTFGGGTKLEIK1591 BCMA linker GGGGSGGGGSGGGGS 1592 CD70 VHQVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLKWMGWINTYTGEPTYADAFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDYGDYGMDYWGQGTTVTVSS 1593 CD70 VLDIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY CQHSREVPWTFGQGTKVEIK 1594CD70 linker GGGGSGGGGSGGGGSG 1595 CD19 VHEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIVVGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS 1596 CD19 VLDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGN TLPYTFGGGTKLEIT 1597CD19 linker GSTSGSGKPGSGEGSTKG

Note Regarding Illustrative Examples

While the present disclosure provides descriptions of various specificaspects for the purpose of illustrating various aspects of the presentinvention and/or its potential applications, it is understood thatvariations and modifications will occur to those skilled in the art.Accordingly, the invention or inventions described herein should beunderstood to be at least as broad as they are claimed, and not as morenarrowly defined by particular illustrative aspects provided herein.

Any patent, publication, or other disclosure material identified hereinis incorporated by reference into this specification in its entiretyunless otherwise indicated, but only to the extent that the incorporatedmaterial does not conflict with existing descriptions, definitions,statements, or other disclosure material expressly set forth in thisspecification. As such, and to the extent necessary, the expressdisclosure as set forth in this specification supersedes any conflictingmaterial incorporated by reference. Any material, or portion thereof,that is said to be incorporated by reference into this specification,but which conflicts with existing definitions, statements, or otherdisclosure material set forth herein, is only incorporated to the extentthat no conflict arises between that incorporated material and theexisting disclosure material. Applicants reserve the right to amend thisspecification to expressly recite any subject matter, or portionthereof, incorporated by reference herein.

What is claimed is:
 1. A method for producing an engineered human Tcell, the method comprising delivering to a human primary T cell: (a) aRNA-guided nuclease; (b) a guide RNA (gRNA) targeting a site in a T cellreceptor alpha chain constant region (TRAC) gene (TRAC gRNA), whereinthe TRAC gRNA comprises a nucleotide sequence, which targets thenucleotide sequence of SEQ ID NO:76; (c) a gRNA targeting a site in abeta-2-microglobulin (B2M) gene (B2M gRNA); and (d) a vector comprisinga nucleic acid comprising a nucleotide sequence that comprises (i) afirst segment that is homologous to the TRAC gene locus left of the sitetargeted by the TRAC gRNA, (ii) a second segment encoding a chimericantigen receptor (CAR), and (iii) a third segment that is homologous tothe TRAC gene locus right to the site targeted by the TRAC gRNA, whereinthe CAR comprises (i) an ectodomain that comprises an anti-CD70 antibodysingle-chain variable fragment (scFv), wherein the anti-CD70 scFvcomprises a variable heavy chain comprising the amino acid sequence ofSEQ ID NO: 1592, and a variable light chain comprising the amino acidsequence of SEQ ID NO: 1593, (ii) a CD8 transmembrane domain, and (iii)an endodomain that comprises a CD28 or 41BB co-stimulatory domain and aCD3z co-stimulatory domain, thereby producing an engineered human T cellexpressing the CAR.
 2. The method of claim 1, wherein the TRAC gRNAcomprises the nucleotide sequence of SEQ ID NO:
 152. 3. The method ofclaim 2, wherein the TRAC gRNA comprises the nucleotide sequence of SEQID NO: 1342 or SEQ ID NO:
 1343. 4. The method of claim 1, wherein theB2M gRNA comprises a nucleotide sequence, which targets the nucleotidesequence of SEQ ID NO:
 417. 5. The method of claim 4, wherein the B2MgRNA comprises the nucleotide sequence of SEQ ID NO:
 466. 6. The methodof claim 5, wherein the B2M gRNA comprises the nucleotide sequence ofSEQ ID NO: 1344 or SEQ ID NO:
 1345. 7. The method of claim 1, whereinthe anti-CD70 scFv comprises the amino acid sequence of SEQ ID NO: 1499or SEQ ID NO:
 1500. 8. The method of claim 7, wherein the anti-CD70 scFvcomprises the amino acid sequence of SEQ ID NO:
 1500. 9. The method ofclaim 1, wherein the endodomain comprises the 41BB co-stimulatory domainand the CD3z co-stimulatory domain.
 10. The method of claim 1, whereinthe CAR comprises the amino acid sequence of SEQ ID NO: 1449, 1450, or1276.
 11. The method of claim 10, wherein the CAR comprises the aminoacid sequence of SEQ ID NO:
 1276. 12. The method of claim 1, wherein thefirst segment comprises the nucleotide sequence of SEQ ID NO:
 1325. 13.The method of claim 1, wherein the third segment comprises thenucleotide sequence of SEQ ID NO:
 1326. 14. The method of claim 1,wherein the vector comprises the nucleotide sequence of SEQ ID NO: 1396.15. The method of claim 1, wherein the RNA-guided nuclease is a Cas9nuclease.
 16. The method of claim 15, wherein the Cas9 nuclease is aStreptococcus pyogenes Cas9 nuclease.
 17. The method of claim 1, whereinthe vector is an adeno-associated viral (AAV) vector.
 18. The method ofclaim 17, wherein the AAV vector is an AAV serotype 6 (AAV6) vector. 19.The method of claim 18, wherein the AAV vector comprises the nucleotidesequence of SEQ ID NO: 1396.